Macrocyclic FLT3 kinase inhibitors

ABSTRACT

The present invention relates to macrocylic compounds and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of FLT3 (FMS-Related Tyrosine kinase 3). Moreover, the present invention provides processes for the preparation of the disclosed compounds, as well as methods of using them, for instance as a medicine, in particular for the treatment of cell proliferative disorders, such as cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is filed under 35 U.S.C. §111 as a divisional ofU.S. application Ser. No. 14/347,750, filed on Mar. 27, 2014, which is aNational Stage Entry of International Application No. PCT/EP2012/069252,filed on Sep. 28, 2012, which designates the United States and claimsthe benefit of European Application No. PCT/EP2011/067084, filed on Sep.30, 2011, the contents of which are hereby incorporated by reference intheir entirety.

FIELD OF THE INVENTION

The present invention relates to macrocylic compounds and compositionscontaining said compounds acting as kinase inhibitors, in particular asinhibitors of FLT3 (FMS-Related Tyrosine kinase 3). Moreover, thepresent invention provides processes for the preparation of thedisclosed compounds, as well as methods of using them, for instance as amedicine, in particular for the treatment of cell proliferativedisorders, such as cancer.

BACKGROUND OF THE INVENTION

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a wide variety of signaltransduction processes in the cell. They have been shown to be keyregulators in most cellular functions including proliferation, cellmetabolism, cell survival, apoptosis, DNA damage repair, cell motility,. . . The protein kinase activity is based on phosphorylation eventswhich act as molecular on/off switches that can modulate or regulate thetarget protein's biological function. Phosphorylation of target proteinsoccurs in response to a variety of extracellular signals (hormones,neurotransmitters, growth and differentiation factors, etc.), cell cycleevents, environmental or nutritional stresses etc. The appropriateprotein kinase functions in signalling pathways to activate orinactivate, for example, a metabolic enzyme, regulatory protein,receptor, cytoskeletal protein, ion channel or pump, or transcriptionfactor. Uncontrolled signalling due to defective control of proteinphosphorylation has been implicated in a number of diseases, including,for example, inflammation, allergies, immune diseases, CNS disorders,angiogenesis. Furthermore, it is not surprising that they often becomeoncogenes, thereby having major implications in multiple cancers, due totheir crucial functions in apoptosis, DNA damage repair, proliferation,. . .

Amongst the families of protein kinases, one particular example is thereceptor tyrosine kinase class III family including FLT3. FLT3 (FMS-liketyrosine kinase 3), also referred to as fetal liver kinase-2 (flk-2) orSTK-I, is mainly expressed on the surface of hematopoietic stem andprogenitor cells, in particular early myeloid and lympoid progenitorcells. It binds to Flt3L to form homodimers which activate signallinginvolved in proliferation, differentiation and apoptosis ofhematopoietic stem and progenitor cells during normal hematopoiesis.Said dimerization results in activation of its tyrosine kinase domain,receptor autophosphorylation and subsequent recruitment of downstreamsignalling molecules such as the p85 subunit of Pl₃K(phosphatidylinositol 3 kinase), PLC-gamma (Phospholipase-C gamma),STAT5a (signal transducer and activator of transcription 5a), and SRCfamily tyrosine kinases (Gilliland and Griffin, Blood (2002) 100(5),1532-42; Drexler, Leukemia (1996) 10(4), 588-99 and Ravandi et al., ClinCancer Res. (2003) 9(2), 535-50). Activation of these downstreamsignalling molecules by phosphorylation leads to the proliferative andpro-survival effects of FLT3 (Gilliland and Griffin (2002) and Levis andSmall, Leukemia (2003) 17(9), 1738-52).

In hematological malignancies, FLT3 is expressed at high levels or FLT3mutations cause an uncontrolled induction of the FLT3 receptor anddownstream molecular pathway. Hematological malignancies includeleukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (alsocalled Hodgkin's lymphoma), and myeloma—for instance, acute lymphocyticleukemia (ALL), acute myeloid leukemia (AML), acute promyelocyticleukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), chronic neutrophilic leukemia (CNL), acuteundifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL),prolymphocytic leukemia (PML), juvenile myelomonocyctic leukemia (JMML),adult T-cell ALL, AML with trilineage myelodysplasia (AML/TMDS), mixedlineage leukemia (MLL), myelodysplastic syndromes (MDSs),myeloproliferative disorders (MPD), multiple myeloma, (MM) and myeloidsarcoma (Kottaridis, P. D., R. E. Gale, et al. (2003). “Flt3 mutationsand leukaemia.” Br J Haematol 122(4): 523-38). Myeloid sarcoma is alsoassociated with FLT3 mutations (Ansari-Lari, Ali et al. FLT3 mutationsin myeloid sarcoma. British Journal of Haematology. 2004 September126(6):785-91).

Mutations of FLT3 have been detected in about 30% of patients with acutemyelogenous leukemia and a small number of patients with acutelymphomatic leukemia or myelodysplastic syndrome. Patients with FLT3mutations tend to have a poor prognosis, with decreased remission timesand disease free survival. There are two known types of activatingmutations of FLT3. One is a duplication of 4-40 amino acids in thejuxtamembrane region (ITD mutation) of the receptor (25-30% of patients)and the other is a point mutation in the kinase domain (5-7% ofpatients). These mutations most often involve small tandem duplicationsof amino acids within the juxtamembrane domain of the receptor andresult in tyrosine kinase activity. Expression of a mutant FLT3 receptorin murine marrow cells results in a lethal myeloproliferative syndrome,and preliminary studies (Blood. 2002; 100: 1532-42) suggest that mutantFLT3 cooperates with other leukemia oncogenes to confer a moreaggressive phenotype.

Specific inhibitors of FLT3 kinase therefore present an attractivestrategy for the treatment of hematopoietic disorders and hematologicalmalignancies. It was as such an object of the present invention toprovide compounds and compositions comprising said compounds, acting asinhibitors of receptor tyrosine kinases, in particular as inhibitors ofFLT3 (FMS-Related Tyrosine kinase 3).

We have now found that macrocyclic pyrazolopyrimidines can act as kinaseinhibitors in particular FLT3 kinase inhibitors.

Several (non-macrocyclic) pyrazolopyrimidines have already beensuggested as kinase inhibitors for the treatment of proliferativediseases such as cancer. For example:

-   -   WO2007044420: inhibition of CDK—treatment of cancer, . . .    -   WO2009097446: inhibition of PI₃ Kinase—treatment of cancer    -   WO2010036380: inhibition of PI₃ Kinase—treatment of cancer    -   WO2008037477: inhibition of PI₃ Kinase—treatment of        proliferative diseases, . . .    -   WO2006050946: inhibition of c-Abl, c-Src, . . . —treatment of        proliferative diseases    -   WO2011003065: inhibition of JAK—treatment of cancer, leukemia, .        . .    -   WO2010119284: inhibition of FGFR kinase—treatment of cancer

However, none of the compounds disclosed in said references have beenshown to have FLT3 inhibitory activity. Furthermore, the currentlydeveloped FLT3 kinase inhibitors, do not comprise macrocyclicpyrazolopyrimidine moieties (see for example WO2004039782, WO2007048088,WO2008016665, WO2009017795, WO2009109071). The compounds disclosedherein are therefore distinguishable from the prior art compounds instructure, pharmacological activity, potency and kinase selectivity.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a compound of FormulaI or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug,salt, hydrate, N-oxide form, or solvate thereof,

Wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, then A₂ is N;and wherein when A₂ is C, then A₁ is N;

R₁ and R₇ are each independently selected from —H, -halo, —OH,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —NR₉R₁₀, —(C═O)—R₄, —SO₂—R₄,—CN, —NR₉—SO₂—R₄, —C₃₋₆cycloalkyl, and -Het₆; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —NR₁₁R₁₂, —O—C₁₋₆alkyl, and—S—C₁₋₆alkyl;

R₂ is selected from —H, -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)—O—C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈,-Het₃, —(C═O)—Het₃, —SO₂—C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,-Het₃, —Ar₂, and —NR₁₃R₁₄;

R₃ is selected from —H, -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)—O—C₁₋₆alkyl, -Het₂,—C₃₋₆cycloalkyl-(C═O)-Het₂, —(C═O)—NR₂₉R₃₀, and —SO₂—C₁₋₆alkyl; whereineach of said C₁₋₆alkyl is optionally and independently substituted withfrom 1 to 3 substituents selected from -halo, —OH, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₁₅R₁₆, -Het₂, and —Ar₃;

R₄ is independently selected from -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H —C₁₋₆alkyl, —C₃₋₆cycloalkyl; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —OC₁₋₆alkyl, —SC₁₋₆alkyl, -Het₅,and —NR₃₁R₃₂;

R₆ is selected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₃₃R₃₄, and -Het₈;

R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄ are eachindependently selected from —H, —O, —C₁₋₆alkyl, and Het₁; wherein eachof said C₁₋₆alkyl is optionally and independently substituted with from1 to 3 substituents selected from -halo, —OH, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₃₅R₃₆, -Het₇, and —Ar₄;

R₃₅ and R₃₆ are each independently selected from —H, —O, and C₁₋₆alkyl;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH,—O—C₁₋₆alkyl, and —S—C₁₋₆alkyl;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-, —(C═O)—,—NR₃—(C═O)—, —C₁₋₆alkyl-NR₃—(C═O)—, —NR₃—(C═O)—NR₃₅—, —NR₃—C₁₋₆alkyl-,—NR₃—, and —NR₃—SO₂—; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from-halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, and —NR₂₃R₂₄;

X₂ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-, —(C═O)—,—NR₂—(C═O)—, —NR₂—C₁₋₆alkyl-, —NR₂—, and —SO₂—NR₂—; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, and —NR₂₅R₂₆;

Y is selected from a direct bond, —CHR₆—, —O—, —S—, and —NR₅—;

Ar₂, Ar₃, and Ar₄ are each independently a 5- or 6-membered aromaticheterocycle optionally comprising 1 or 2 heteroatoms selected from O, Nand S; wherein each of said Ar₂, Ar₃, and Ar₄ is optionally andindependently substituted with from 1 to 3 substituents selected from—NR₁₉R₂₀, —C₁₋₆alkyl, —O—C₁₋₆alkyl, and —S—C₁₋₆alkyl;

_(Het1), Het₂, Het₃, Het₄, Het₅, Het₆, Het₇ and Het₈ are eachindependently a 5- or 6-membered monocyclic heterocycle having from 1 to3 heteroatoms selected from O, N and S, wherein each heterocycle isoptionally substituted with from 1 to 3 substituents selected from—C₁₋₆alkyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, and —NR₂₁R₂₂; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3-halo;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N;

m and n are each independently 1, 2, 3, or 4.

In a specific embodiment, the present invention provides a compound asdefined herein, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, then A₂ is N;and wherein when A₂ is C, then A₁ is N;

R₁ is selected from —H, -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —NR₉R₁₀,—(C═O)—R₄, —CN, —NR₉—SO₂—R₄, and -Het₆; wherein each of said C₁₋₆alkylis optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, and —NR₁₁R₁₂;

R₇ is selected from —H, and -halo;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈, —(C═O)-Het₃, and—SO₂—C₁₋₆alkyl; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from-halo, —OH, —O—C₁₋₆alkyl, -Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)-Het₂,—(C═O)—NR₂₉R₃₀, and —SO₂—C₁₋₆alkyl; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, —OH, and —O—C₁₋₆alkyl;

R₄ is independently selected from —OH, —O—C₁₋₆alkyl, —NR₁₇R₁₈, and-Het₄;

R₅ is selected from —H, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —OC₁₋₆alkyl, -Het₅, and—NR₃₁R₃₂;

R₆ is selected from —OH, and —NR₃₃R₃₄;

R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₇, R₁₈, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂,R₃₃, R₃₄ are each independently selected from —H, —C₁₋₆alkyl, —NR₃₅R₃₆or Het₁; wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH, and-Het₇;

R₃₅ and R₃₆ are each independently selected from —H, —O, and C₁₋₆alkyl;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH,—O—C₁₋₆alkyl, and —S—C₁₋₆alkyl;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-, —(C═O)—,—NR₃—(C═O)—, —C₁₋₆alkyl-NR₃—(C═O)—, —NR₃—(C═O)—NR₃₅—, —NR₃—C₁₋₆alkyl-,and —NR₃—SO₂—;

X₂ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —(C═O)—NR₂—, and—NR₂—C₁₋₆alkyl-;

Y is selected from a direct bond, —CHR₆—, —O—, —S—, and —NR₅—;

Het₁, Het₂, Het₃, Het₄, Het₅, Het₆, and Het₇ are each independently a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatomsselected from O, N and S, wherein each heterocycle is being optionallysubstituted with from 1 to 3 —C₁₋₆alkyl; each of said C₁₋₆alkyl beingoptionally and independently substituted with from 1 to 3 -halo

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N;

m and n are each independently 1, 2, 3, or 4.

In another specific embodiment, the present invention provides acompound as defined herein wherein,

A₁ and A₂ are selected from C and N; wherein when A₁ is C, then A₂ is N;and wherein when A₂ is C, then A₁ is N;

R₁ is selected from —H, -halo, —OH, —C₁₋₂alkyl, —O—C₁₋₂alkyl, —NR₉R₁₀,—(C═O)—R₄, —CN, —NR₉—SO₂—R₄, and -Het₆; wherein each of said C₁₋₂alkylis optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, and —NR₁₁R₁₂;

R₇ is selected from —H, and -halo;

R₂ is selected from —H, —C₁₋₃alkyl, —(C═O)—NR₂₇R₂₈, —(C═O)-Het₃, and—SO₂—C₁₋₃alkyl; wherein each of said C₁₋₃alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from-halo, —OH, —O—CH₃, -Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₂alkyl, —(C═O)—C₁₋₂alkyl, —(C═O)-Het₂,—(C═O)—NR₂₉R₃₀, and —SO₂—C₁₋₂alkyl; wherein each of said C₁₋₂alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, —OH, and —O—CH₃;

R₄ is selected from —OH, —O—CH₃, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H —C₁₋₃alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₃alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —OCH₃, -Het₅, and —NR₃₁R₃₂;

R₆ is selected from —OH, and —NR₃₃R₃₄;

R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₃₁, R₃₂, R₃₃, and R₃₄ are eachindependently selected from —H and —CH₃;

R₁₇, R₁₈, R₂₇, and R₂₈ are each independently selected from —H and—C₁₋₂alkyl, each of said —C₁₋₂alkyl being optionally and independentlysubstituted with from 1 to 3 substituents selected from —OH,-halo-NR₃₅R₃₆ and -Het₇

R₂₉ and R₃₀, are each independently selected from —H, —OH and —OCH₃;

R₃₅ and R₃₆ are each independently selected from —H, —O, and C₁₋₆alkyl;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH,—O—C₁₋₆alkyl, and —S—C₁₋₆alkyl;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —(C═O)—S—C₁₋₆alkyl-,—NR₃—(C═O)—, —C₁₋₆alkyl-NR₃—(C═O)—, —NR₃—(C═O)—NR₃₅—, —NR₃—C₁₋₆alkyl-,and —NR₃—SO₂—C₁₋₆alkyl-;

X₂ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —(C═O)—NR₂—, and—NR₂—C₁₋₆alkyl-;

Y is selected from a direct bond, —CHR₆—, —O—, —S—, and —NR₅—;

Het₁ is selected from -piperidinyl and -piperazinyl; each of said Het₁being substituted with C₁₋₂alkyl; each of said C₁₋₂alkyl beingoptionally and independently substituted with from 1 to 3 -halo;

Het₂ is -piperidinyl-CH₃;

Het₃ is selected from -piperazinyl, and -morpholinyl;

Het₄, is selected from -piperazinyl, and -morpholinyl; each of said Het₄being optionally and independently substituted with C₁₋₂alkyl; each ofsaid C₁₋₂alkyl being optionally and independently substituted with from1 to 3 -halo;

Het₅ is -morpholinyl;

Het₆, is -piperazinyl;

Het₇ is -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N

m and n are each independently 1, 2, 3, or 4.

In yet a further embodiment, the present invention provides a compound adefined herein, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, than A₂ is N;and wherein when A₂ is C, than A₁ is N;

R₁ is selected from —H, -halo, —C₁₋₆alkyl, —OC₁₋₆alkyl, and —(C═O)—R₄;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 -halo;

R₇ is —H;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—O—C₁₋₆alkyl, and —(C═O)-Het₃;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from —OH,—OC₁₋₆alkyl, -Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₆alkyl, and —(C═O)-Het₂; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents —OH;

R₄ is selected from —OH, —O—C₁₋₆alkyl, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from —OH, and -Het₅;

R₁₃, R₁₄, R₁₇, R₁₈, R₁₉ and R₂₀ are each independently selected from —H,—O, —C₁₋₆alkyl, and Het₁;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —NR₃—(C═O)—,—C₁₋₆alkyl-NR₃—(C═O)—, and —NR₃—C₁₋₆alkyl-;

X₂ is selected from —O—C₁₋₆alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₆alkyl-;

Y is selected from a direct bond, —O—, —S—, and —NR₅—;

Het₁, Het₂, Het₃, Het₄ and Het₅ are each independently a 5- or6-membered monocyclic heterocycle having from 1 to 3 heteroatomsselected from O, N and S, wherein each heterocycle is being optionallysubstituted with from 1 to 3 —C₁₋₆alkyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N;

m and n are each independently 1, 2, 3, or 4.

In another specific embodiment, the present invention provides acompound as defined herein, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, than A₂ is N;and wherein when A₂ is C, than A₁ is N

R₁ is selected from —H, -halo, —CF₃, —OC₁₋₆alkyl, and —(C═O)—R₄;

R₇ is —H;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—O—C₁₋₆alkyl, and —(C═O)-Het₃;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from —OH,—OC₁₋₆alkyl, -Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₆alkyl, and —(C═O)-Het₂; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 —OH;

R₄ is selected from —OH, —OC₁₋₆alkyl, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from —OH, and -Het₅;

R₁₃ and R₁₄ are each independently selected from —H, and —C₁₋₆alkyl;

R₁₇ and R₁₈ are each independently selected from —H, —C₁₋₆alkyl, and-Het₁:

R₁₉ and R₂₀ are each independently selected from —O, and —C₁₋₆alkyl;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —NR₃—(C═O)—,—C₁₋₆alkyl-NR₃—(C═O)—, and —NR₃—C₁₋₆alkyl-;

X₂ is selected from —O—C₁₋₆alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₆alkyl-;

Y is selected from a direct bond, —O—, —S—, and —NR₅—;

Het₁, Het₂, Het₃, Het₄ and Het₅ are each independently selected from-morpholinyl, -piperidinyl, -piperazinyl, and pyrrolidinyl, wherein eachheterocycle is optionally substituted with from 1 to 3 —C₁₋₆alkyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N

m and n are each independently 1, 2, 3, or 4.

In yet a further embodiment, the present invention provides a compoundaccording to this invention, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, than A₂ is N;and wherein when A₂ is C, than A₁ is N

R₁ is selected from —H, -halo, —CF₃, —OCH₃, and —(C═O)—R₄;

R₇ is —H;

R2 is selected from —H, —C₂₋₄alkyl, —(C═O)—O—C₂₋₄alkyl, and —(C═O)-Het₃;wherein each of said C₂₋₄alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from —OH, —OCH₃,-Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₂alkyl, and —(C═O)-Het₂; wherein each ofsaid C₁₋₂alkyl is optionally and independently substituted with from 1to 3 —OH;

R₄ is selected from —OH, —OCH₃, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H, —C₁₋₃alkyl, and —C₃₋₆cycloalkyl; wherein eachC₁₋₃alkyl is optionally substituted with from 1 to 3 substituentsselected from —OH, and -Het₅;

R₁₃ and R₁₄ are —CH₃;

R₁₇ and R₁₈ are each independently selected from —H, —CH₃, and -Het₁;

R₁₉ and R₂₀ are each —O;

X₁ is selected from —C₁₋₆alkyl-, —O—C₂₋₆alkyl-, —NR₃—(C═O)—,—C₁₋₆alkyl-NR₃—(C═O)—, and —NR₃—C₂₋₃alkyl-;

X₂ is selected from —O—C₂alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₃alkyl-;

Y is selected from a direct bond, —O—, —S—, and —NR₅—;

Het₁, Het₂, Het₃, Het₄ and Het₅ are each independently selected from-morpholinyl, -piperidinyl, -piperazinyl, and pyrrolidinyl, wherein eachheterocycle is optionally substituted with from 1 to 3 —CH₃;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N

m and n are each independently 1, 2, 3, or 4.

In a further specific embodiment, the invention provides a compound asdefined herein, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, than A₂ is N;and wherein when A₂ is C, than A₁ is N;

R₁ is selected from —H, -halo, —CF₃, —OCH₃, —(C═O)—OH, —(C═O)—OCH₃,—(C═O)-Het₄, —(C═O)—NH-Het₄, —(C═O)—NH₂, and —(C═O)—NH—CH₃;

R₇ is —H;

R₂ is selected from —H, —C₂₋₄alkyl, —(C═O)—O—C₂alkyl, and —(C═O)-Het₃;wherein each C₂₋₄alkyl is optionally and independently substituted with1 substituent selected from —OH, —OCH₃, -Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₂alkyl, and —(C═O)-Het₂; wherein saidC₁₋₂alkyl is optionally and independently substituted with 1 —OH;

R₅ is selected from —H, —C₁₋₃alkyl, and —C₃₋₆cycloalkyl; wherein eachC₁₋₃alkyl is optionally and independently substituted with 1 to 3substituents selected from —OH, and -Het₅;

R₁₃ and R₁₄ are —CH₃;

X₁ is selected from —C₁₋₆alkyl-, —O—C₂₋₆alkyl-, —NR₃—(C═O)—,—C₁₋₆alkyl-NR₃—(C═O)—, and —NR₃—C₂alkyl-;

X₂ is selected from —O—C₂alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₃alkyl-;

Y is selected from a direct bond, —O—, —S—, and —NR₅—;

Ar₃ is phenyl substituted with —NO₂;

Het₂ is -piperidinyl substituted with —CH₃;

Het₃ is selected from -morpholinyl, and -piperazinyl;

Het₄ is selected from -morpholinyl, -piperidinyl, and -piperazinyl;wherein said -piperidinyl and -piperazinyl are substituted with —CH₃;

Het₅ is selected from -morpholinyl, and -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N

m and n are each independently 1, 2, 3, or 4.

The invention further provides a compound as defined herein, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, then A₂ is N;and wherein when A₂ is C, then A₁ is N;

R₁ and R₇ are each independently selected from —H, -halo, —C₁₋₆alkyl,—O—C₁₋₆alkyl, and —(C═O)—R₄; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, and —OH;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈, and —(C═O)-Het₃;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH, and—NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₆alkyl, and —(C═O)-Het₂; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with —OH;

R₄ is independently selected from —OH, and —NR₁₇R₁₈;

R₅ is selected from —H —C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —OC₁₋₆alkyl, -Het₅, and—NR₃₁R₃₂;

R₁₃, R₁₄, R₁₇, R₁₈, R₂₇, R₂₈, R₃₁, R₃₂ are each independently selectedfrom —H, and —C₁₋₆alkyl; wherein each of said C₁₋₆alkyl is optionallyand independently substituted with from 1 to 3 substituents selectedfrom -halo, —NR₃₅R₃₆, and -Het₇;

R₃₅ and R₃₆ are each —C₁₋₆alkyl;

X₁ is selected from —O—C₁₋₆alkyl-, —(C═O)—, —NR₃—(C═O)—,—C₁₋₆alkyl-NR₃—(C═O)—, and —NR₃—;

X₂ is selected from —O—C₁₋₆alkyl-, and —NR₂—;

Y is selected from a direct bond, —O—, and —NR₅—;

Het₃ is -piperazinyl

Het₂ is -piperidinyl substituted with —CH₃;

Het₅ is selected from -morpholinyl and -pyrrolidinyl;

Het₇ is -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N;

m and n are each independently 1, 2, 3, or 4.

In a preferred embodiment, the present invention provides a compound asdefined herein, wherein

A₁ is N; and A₂ is C;

R₁ and R₇ are each independently selected from —H, —C₁₋₆alkyl,—O—C₁₋₆alkyl, and —(C═O)—R₄; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, and —OH;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from —OH;

R₃ is selected from —H, —C₁₋₆alkyl, and —(C═O)-Het₂; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with —OH;

R₄ is independently selected from —OH, and —NR₁₇R₁₈;

R₅ is selected from —H —C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —OC₁₋₆alkyl, and -Het₅;

R₁₇, R₁₈, R₂₇, and R₂₈ are each independently selected from —H, and—C₁₋₆alkyl; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from—NR₃₅R₃₆, and -Het₇;

R₃₅ and R₃₆ are each —C₁₋₆alkyl;

X₁ is selected from —O—C₁₋₆alkyl-, —NR₃—(C═O)—, and —NR₃—;

X₂ is selected from —O—C₁₋₆alkyl-, and —NR₂—;

Y is selected from a direct bond, —O—, and —NR₅—;

Het₂ is -piperidinyl substituted with —CH₃;

Het₅ is selected from -morpholinyl and -pyrrolidinyl;

Het₇ is -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each C;

m and n are each independently 1, 2, 3, or 4.

In another preferred embodiment, the present invention provides acompound as defined herein, wherein

A₁ is N; and A₂ is C;

R₁ and R₇ are each —H;

R₂ is selected from —H, —(C═O)—NR₂₇R₂₈ and —C₁₋₆alkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 —OH;

R₅ is selected from —H and —C₁₋₆alkyl; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 -Het₅;

R₂₇, and R₂₈ are each independently selected from —H, and —C₁₋₆alkyl;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from —NR₃₅R₃₆, and-Het₇;

R₃₅ and R₃₆ are each —C₁₋₆alkyl;

X₁ is selected from —O—CH₂—;

X₂ is selected from —O—CH₂—, and —NR₂—;

Y is —NR₅—;

Het₅ is selected from -morpholinyl and -pyrrolidinyl;

Het₇ is -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each C;

m is 1; and

n is selected from 1, 2 and 3.

In a particular embodiment, the present invention provides a compoundselected from the list comprising:

more in particular

In a preferred embodiment, the present invention provides a compound asdefined herein above, wherein the pyrazolopyrimidine moiety is linked tothe aryl or heteroaryl moiety at position Z₄ and wherein R₇ is linked tothe aryl or heteroaryl moiety at position Z₅ in accordance with FormulaI.

In a further aspect, the present invention provides a compound accordingto this invention for use as a human or veterinary medicine. More inparticular, it provides the use of a compound according to thisinvention for the manufacture of a medicament for the treatment of cellproliferative disorders, such as cancer.

The present invention further provides a pharmaceutical compositioncomprising a compound according to this invention, suitable for use as ahuman or veterinary medicine.

In yet a further aspect, the present invention provides the use of acompound or a composition according to this invention, suitable forinhibiting the activity of a kinase; in particular a FLT3 kinase.

It further provides the use of a compound or a composition according tothis invention for the prevention and/or or treatment of cellproliferative disorders, such as cancer.

In a further aspect, the present invention provides a method for theprevention and/or treatment of cell proliferative disorders such ascancer; said method comprising administering to a subject in needthereof a compound or a composition according to this invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be further described. In the followingpassages, different aspects of the invention are defined in more detail.Each aspect so defined may be combined with any other aspect or aspectsunless clearly indicated to the contrary. In particular, any featureindicated as being preferred or advantageous may be combined with anyother feature or features indicated as being preferred or advantageous.

Unless a context dictates otherwise, asterisks are used herein toindicate the point at which a mono- or bivalent radical depicted isconnected to the structure to which it relates and of which the radicalforms part.

As already mentioned hereinbefore, in a first aspect the presentinvention provides compounds of Formula I, or a stereoisomer, tautomer,racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, orsolvate thereof,

wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, then A₂ is N;and wherein when A₂ is C, then A₁ is N;

R₁ and R₇ are each independently selected from —H, -halo, —OH,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —NR₉R₁₀, —(C═O)—R₄, —SO₂—R₄,—CN, —NR₉—SO₂—R₄, —C₃₋₆cycloalkyl, and -Het₆; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —NR₁₁R₁₂, —O—C₁₋₆alkyl, and—S—C₁₋₆alkyl;

R₂ is selected from —H, -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)—O—C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈,-Het₃, —(C═O)-Het₃, —SO₂—C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,-Het₃, —Ar₂, and —NR₁₃R₁₄;

R₃ and R₃₅ are each independently selected from —H, -halo, —OH,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl,—(C═O)—O—C₁₋₆alkyl, -Het₂, —C₃₋₆cycloalkyl-(C═O)-Het₂, —(C═O)—NR₂₉R₃₀,and —SO₂—C₁₋₆alkyl; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from-halo, —OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —NR₁₅R₁₆, -Het₂, and —Ar₃;

R₄ is independently selected from -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H —C₁₋₆alkyl, —C₃₋₆cycloalkyl; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —OC₁₋₆alkyl, —SC₁₋₆alkyl, -Het₅,and —NR₃₁R₃₂;

R₆ is selected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₃₃R₃₄, and -Het₈;

R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄ are eachindependently selected from —H, —O, —C₁₋₆alkyl, and Het₁; wherein eachof said C₁₋₆alkyl is optionally and independently substituted with from1 to 3 substituents selected from -halo, —OH, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₃₅R₃₆, -Het₇, and —Ar₄;

R₃₅ and R₃₆ are each independently selected from —H, —O, and C₁₋₆alkyl;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH,—O—C₁₋₆alkyl, and —S—C₁₋₆alkyl;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-, —(C═O)—,—NR₃—(C═O)—, —C₁₋₆alkyl-NR₃—(C═O)—, —NR₃—(C═O)—NR₃₅—, —NR₃—C₁₋₆alkyl-,—NR₃—, and —NR₃—SO₂—; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from-halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, and —NR₂₃R₂₄;

X₂ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-, —(C═O)—,—NR₂—(C═O)—, —NR₂—C₁₋₆alkyl-, —NR₂—, and —SO₂—NR₂—; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, and —NR₂₅R₂₆;

Y is selected from a direct bond, —CHR₆—, —O—, —S—, and —NR₅—;

Ar₂, Ar₃, and Ar₄ are each independently a 5- or 6-membered aromaticheterocycle optionally comprising 1 or 2 heteroatoms selected from O, Nand S; wherein each of said Ar₂, Ar₃, and Ar₄ is optionally andindependently substituted with from 1 to 3 substituents selected from—NR₁₉R₂₀, —C₁₋₆alkyl, —O—C₁₋₆alkyl, and —S—C₁₋₆alkyl;

Het₁, Het₂, Het₃, Het₄, Het₅, Het₆, Het₇ and Het₈ are each independentlya 5- or 6-membered monocyclic heterocycle having from 1 to 3 heteroatomsselected from O, N and S, wherein each heterocycle is optionallysubstituted with from 1 to 3 substituents selected from —C₁₋₆alkyl,—OC₁₋₆alkyl, —SC₁₋₆alkyl, and —NR₂₁R₂₂; wherein each of said C₁₋₆alkylis optionally and independently substituted with from 1 to 3 -halo;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N;

m and n are each independently 1, 2, 3, or 4.

When describing the compounds of the invention, the terms used are to beconstrued in accordance with the following definitions, unless a contextdictates otherwise:

The term “alkyl” by itself or as part of another substituent refers tofully saturated hydrocarbon radicals. Generally, alkyl groups of thisinvention comprise from 1 to 6 carbon atoms. Alkyl groups may be linearor branched and may be substituted as indicated herein. When a subscriptis used herein following a carbon atom, the subscript refers to thenumber of carbon atoms that the named group may contain. Thus, forexample, C₁₋₆alkyl means an alkyl of one to six carbon atoms. Examplesof alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl, and itsisomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers,hexyl and its isomers. C₁-C₆ alkyl includes all linear, branched, orcyclic alkyl groups with between 1 and 6 carbon atoms, and thus includesmethyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl,i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers,cyclopentyl, and cyclohexyl.

The term “optionally substituted alkyl” refers to an alkyl groupoptionally substituted with one or more substituents (for example 1 to 3substituents, for example 1, 2 or 3 substituents or 1 to 2 substituents)at any available point of attachment. Non-limiting examples of suchsubstituents include -halo, —OH, primary and secondary amides,—O—C₁₋₆alkyl, —S—C₁₋₆alkyl, heteroaryl, aryl, and the like.

The term “cycloalkyl” by itself or as part of another substituent is acyclic alkyl group, that is to say, a monovalent, saturated, orunsaturated hydrocarbyl group having a cyclic structure. Cycloalkylincludes all saturated or partially saturated (containing 1 or 2 doublebonds) hydrocarbon groups having a cyclic structure. Cycloalkyl groupsmay comprise 3 or more carbon atoms in the ring and generally, accordingto this invention comprise from 3 to 6 atoms. Examples of cycloalkylgroups include but are not limited to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl.

Where alkyl groups as defined are divalent, i.e., with two single bondsfor attachment to two other groups, they are termed “alkylene” groups.Non-limiting examples of alkylene groups includes methylene, ethylene,methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene,1,2-dimethylethylene, pentamethylene and hexamethylene.

Generally, alkylene groups of this invention preferably comprise thesame number of carbon atoms as their alkyl counterparts. Where analkylene or cycloalkylene biradical is present, connectivity to themolecular structure of which it forms part may be through a commoncarbon atom or different carbon atom. To illustrate this applying theasterisk nomenclature of this invention, a C₃ alkylene group may be forexample *—CH₂CH₂CH₂—*, *—CH(—CH₂CH₃)—*, or *—CH₂CH(—CH₃)—*. Likewise aC₃ cycloalkylene group may be

The terms “heterocycle” as used herein by itself or as part of anothergroup refer to non-aromatic, fully saturated or partially unsaturatedcyclic groups (for example, 3 to 6 membered monocyclic ring systems)which have at least one heteroatom in at least one carbonatom-containing ring. Each ring of the heterocyclic group containing aheteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogenatoms, oxygen atoms and/or sulfur atoms. An optionally substitutedheterocyclic refers to a heterocyclic having optionally one or moresubstituents (for example 1 to 4 substituents, or for example 1, 2, 3 or4), selected from those defined above for substituted alkyl.

Exemplary heterocyclic groups include piperidinyl, azetidinyl,imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl,succinimidyl, 3H-indolyl, isoindolinyl, chromenyl, isochromanyl,xanthenyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl,pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl,piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl,dihydro-2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, phthalazinyl,oxetanyl, thietanyl, 3-dioxolanyl, 1,3-dioxanyl, 2,5-dioximidazolidinyl,2,2,4-piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrehydrothienyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolanyl,1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 6H-1,2,5-thiadiazinyl,2H-1,5,2-dithiazinyl, 2H-oxocinyl, 1H-pyrrolizinyl,tetrahydro-1,1-dioxothienyl, N-formylpiperazinyl, and morpholinyl; inparticular pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl,dioxolanyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl,thiazolidinyl, tetrahydropyranyl, and tetrahydrofuranyl.

The term “aryl” as used herein refers to a polyunsaturated, aromatichydrocarbyl group having a single ring (i.e. phenyl). Aryl is alsointended to include the partially hydrogenated derivatives of thecarbocyclic systems enumerated herein. Non-limiting examples of arylcomprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, 1-, 2-,3-, 4-, 5-, 6-, 7-, or 8-azulenyl, 1- or 2-naphthyl, 1-, 2-, or3-indenyl, 1-, 2-, or 9-anthryl, 1- 2-, 3-, 4-, or 5-acenaphtylenyl, 3-,4-, or 5-acenaphtenyl, 1-, 2-, 3-, 4-, or 10-phenanthryl, 1- or2-pentalenyl, 1, 2-, 3-, or 4-fluorenyl, 4- or 5-indanyl, 5-, 6-, 7-, or8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl,dibenzo[a,d]cylcoheptenyl, and 1-, 2-, 3-, 4-, or 5-pyrenyl; inparticular phenyl.

The aryl ring can optionally be substituted by one or more substituents.An “optionally substituted aryl” refers to an aryl having optionally oneor more substituents (for example 1 to 5 substituents, for example 1, 2,3 or 4) at any available point of attachment, selected from thosedefined above for substituted alkyl.

Where a carbon atom in an aryl group is replaced with a heteroatom, theresultant ring is referred to herein as a heteroaryl ring.

The term “heteroaryl” as used herein by itself or as part of anothergroup refers but is not limited to 5 to 6 carbon-atom aromatic rings inwhich one or more carbon atoms can be replaced by oxygen, nitrogen orsulfur atoms. Non-limiting examples of such heteroaryl, include:pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl,pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl,triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl,thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl,thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl,indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl,isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl,1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl,1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl,1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl,2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl,imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl,2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl,1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,quinoxalinyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl.

An “optionally substituted heteroaryl” refers to a heteroaryl havingoptionally one or more substituents (for example 1 to 4 substituents,for example 1, 2, 3 or 4), selected from those defined above forsubstituted alkyl.

The term “halo” or “halogen” as a group or part of a group is genericfor fluoro, chloro, bromo, or iodo, as well as any suitable isotopethereof.

Whenever the term “substituted” is used in the present invention, it ismeant to indicate that one or more hydrogens on the atom indicated inthe expression using “substituted” is replaced with a selection from theindicated group, provided that the indicated atom's normal valency isnot exceeded, and that the substitution results in a chemically stablecompound, i.e. a compound that is sufficiently robust to surviveisolation to a useful degree of purity from a reaction mixture, andformulation into a therapeutic and/or diagnostic agent

Where groups may be optionally substituted, such groups may besubstituted once or more, and preferably once, twice or thrice.Substituents may be selected from, those defined above for substitutedalkyl.

As used herein the terms such as “alkyl, aryl, or cycloalkyl, each beingoptionally substituted with” or “alkyl, aryl, or cycloalkyl, optionallysubstituted with” refers to optionally substituted alkyl, optionallysubstituted aryl and optionally substituted cycloalkyl.

More generally, from the above, it will be clear to the skilled personthat the compounds of the invention may exist in the form of differentisomers and/or tautomers, including but not limited to geometricalisomers, conformational isomers, E/Z-isomers, stereochemical isomers(i.e. enantiomers and diastereoisomers) and isomers that correspond tothe presence of the same substituents on different positions of therings present in the compounds of the invention. All such possibleisomers, tautomers and mixtures thereof are included within the scope ofthe invention.

In addition, the invention includes isotopically-labelled compounds andsalts, which are identical to compounds of formula (I), but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number most commonlyfound in nature. Examples of isotopes that can be incorporated intocompounds of formula (I) are isotopes of hydrogen, carbon, nitrogen,fluorine, such as ³H, ¹¹C, ¹³N, ¹⁴C, ¹⁵O and ¹⁸F. Suchisotopically-labelled compounds of formula (I) are useful in drug and/orsubstrate tissue distribution assays. For example ¹¹C and ¹⁸F isotopesare particularly useful in PET (Positron Emission Tomography). PET isuseful in brain imaging. Isotopically labeled compounds of formula (I)can generally be prepared by carrying out the procedures disclosedbelow, by substituting a readily available non-isotopically labeledreagent with an isotopically labeled reagent.

Whenever used in the present invention the term “compounds of theinvention” or a similar term is meant to include the compounds ofgeneral Formula I and any subgroup thereof. This term also refers to thecompounds as depicted in Table 1, their derivatives, N-oxides, salts,solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomericforms, optical isomers, analogues, pro-drugs, esters, and metabolites,as well as their quaternized nitrogen analogues. The N-oxide forms ofsaid compounds are meant to comprise compounds wherein one or severalnitrogen atoms are oxidized to the so-called N-oxide.

As used in the specification and the appended claims, the singular forms“a”, “an”, and “the” include plural referents unless the context clearlydictates otherwise. By way of example, “a compound” means one compoundor more than one compound.

The terms described above and others used in the specification are wellunderstood to those in the art.

In a particular embodiment, the present invention provides compounds ofFormula I, or a stereoisomer, tautomer, racemic, metabolite, pro- orpredrug, salt, hydrate, N-oxide form, or solvate thereof,

Wherein one or more of the following applies

A₁ and A₂ are selected from C and N; wherein when A₁ is C, then A₂ is N;and wherein when A₂ is C, then A₁ is N;

R₁ and R₇ are each independently selected from —H, -halo, —OH,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —NR₉R₁₀, —(C═O)—R₄, —SO₂—R₄,—CN, —NR₉—SO₂—R₄, —C₃₋₆cycloalkyl, and -Het₆; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —NR₁₁R₁₂, —O—C₁₋₆alkyl, and—S—C₁₋₆alkyl;

R₂ is selected from —H, -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)—O—C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈,-Het₃, —(C═O)-Het₃, —SO₂—C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,-Het₃, —Ar₂, and —NR₁₃R₁₄;

R₃ is selected from —H, -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)—O—C₁₋₆alkyl, -Het₂,—C₃₋₆cycloalkyl-(C═O)-Het₂, —(C═O)—NR₂₉R₃₀, and —SO₂—C₁₋₆alkyl; whereineach of said C₁₋₆alkyl is optionally and independently substituted withfrom 1 to 3 substituents selected from -halo, —OH, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₁₅R₁₆, -Het₂, and —Ar₃;

R₄ is independently selected from -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H —C₁₋₆alkyl, —C₃₋₆cycloalkyl; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —OC₁₋₆alkyl, —SC₁₋₆alkyl, -Het₅,and —NR₃₁R₃₂;

R₆ is selected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₃₃R₃₄, and -Het₈;

R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄ are eachindependently selected from —H, —O, —C₁₋₆alkyl, and Het₁; wherein eachof said C₁₋₆alkyl is optionally and independently substituted with from1 to 3 substituents selected from -halo, —OH, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₃₅R₃₆, -Het₇, and —Ar₄;

R₃₅ and R₃₆ are each independently selected from —H, —O, and C₁₋₆alkyl;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH,—O—C₁₋₆alkyl, and —S—C₁₋₆alkyl;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-, —(C═O)—,—NR₃—(C═O)—, —C₁₋₆alkyl-NR₃—(C═O)—, —NR₃—(C═O)—NR₃₅—, —NR₃—C₁₋₆alkyl-,—NR₃—, and —NR₃—SO₂—; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from-halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, and —NR₂₃R₂₄;

X₂ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-, —(C═O)—,—NR₂—(C═O)—, —NR₂—C₁₋₆alkyl-, —NR₂—, and —SO₂—NR₂—; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, and —NR₂₅R₂₆;

Y is selected from a direct bond, —CHR₆—, —O—, —S—, and —NR₅—;

Ar₂, Ar₃, and Ar₄ are each independently a 5- or 6-membered aromaticheterocycle optionally comprising 1 or 2 heteroatoms selected from O, Nand S; wherein each of said Ar₂, Ar₃, and Ar₄ is optionally andindependently substituted with from 1 to 3 substituents selected from—NR₁₉R₂₀, —C₁₋₆alkyl, —O—C₁₋₆alkyl, and —S—C₁₋₆alkyl;

Het₁, Het₂, Het₃, Het₄, Het₅, Het₆, Het₇ and Het₈ are each independentlya 5- or 6-membered monocyclic heterocycle having from 1 to 3 heteroatomsselected from O, N and S, wherein each heterocycle is optionallysubstituted with from 1 to 3 substituents selected from —C₁₋₆alkyl,—OC₁₋₆alkyl, —SC₁₋₆alkyl, and —NR₂₁R₂₂; wherein each of said C₁₋₆alkylis optionally and independently substituted with from 1 to 3 -halo;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N;

m and n are each independently 1, 2, 3, or 4.

In particular, X₁, and X₂ as used herein, represent biradicals, whichtaken together with the radicals to which they are attached form amacrocyclic pyrazolopyrimidine compound. Said biradicals may be presentin either of both directions in the macrocyclic pyrazolopyrimidine, butare preferably present in the direction as described below:

Referring to formula I:

-   -   X₁ is selected from the list comprising *—C₁₋₆alkyl-,        *—O—C₁₋₆alkyl-, *—S—C₁₋₆alkyl-, *(C═O)—, —NR₃—(C═O)—*,        *—C₁₋₆alkyl-NR₃—(C═O)—, *—NR₃—(C═O)—NR₃₅—, *—NR₃—C₁₋₆alkyl-,        *—NR₃—, and *—NR₃—SO₂—; wherein said biradical is preferably        attached to the aryl or heteroaryl moiety via *;    -   X₂ is selected from *—C₁₋₆alkyl-, *—O—C₁₋₆alkyl-,        *—S—C₁₋₆alkyl-, *(C═O)—, *—NR₂—(C═O)—, *—NR₂—, and —SO₂—NR₂—*;        wherein said biradical is preferably attached to the        pyrazolopyrimidine moiety via *;

In a specific embodiment, the present invention provides a compound asdefined herein, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, then A₂ is N;and wherein when A₂ is C, then A₁ is N;

R₁ is selected from —H, -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —NR₉R₁₀,—(C═O)—R₄, —CN, —NR₉—SO₂—R₄, and -Het₆; wherein each of said C₁₋₆alkylis optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, and —NR₁₁R₁₂;

R₇ is selected from —H, and -halo;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈, —(C═O)-Het₃, and—SO₂—C₁₋₆alkyl; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from-halo, —OH, —O—C₁₋₆alkyl, -Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)-Het₂,—(C═O)—NR₂₉R₃₀, and —SO₂—C₁₋₆alkyl; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, —OH, and —O—C₁₋₆alkyl;

R₄ is independently selected from —OH, —O—C₁₋₆alkyl, —NR₁₇R₁₈, and-Het₄;

R₅ is selected from —H, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —OC₁₋₆alkyl, -Het₅, and—NR₃₁R₃₂;

R₆ is selected from —OH, and —NR₃₃R₃₄;

R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₇, R₁₈, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂,R₃₃, R₃₄ are each independently selected from —H, —C₁₋₆alkyl, —NR₃₅R₃₆or Het₁; wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH, and-Het₇;

R₃₅ and R₃₆ are each independently selected from —H, —O, and C₁₋₆alkyl;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH,—O—C₁₋₆alkyl, and —S—C₁₋₆alkyl;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —(C═O)—, —S—C₁₋₆alkyl-,—NR₃—(C═O)—, —C₁₋₆alkyl-NR₃—(C═O)—, —NR₃—(C═O)—NR₃₅—, —NR₃—C₁₋₆alkyl-,and —NR₃—SO₂—;

X₂ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —(C═O)—NR₂—, and—NR₂—C₁₋₆alkyl-;

Y is selected from a direct bond, —CHR₆—, —O—, —S—, and —NR₅—;

Het₁, Het₂, Het₃, Het₄, Het₅, Het₆, and Het₇ are each independently a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatomsselected from O, N and S, wherein each heterocycle is being optionallysubstituted with from 1 to 3 —C₁₋₆alkyl; each of said C₁₋₆alkyl beingoptionally and independently substituted with from 1 to 3 -halo

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N;

m and n are each independently 1, 2, 3, or 4.

In another specific embodiment, the present invention provides acompound as defined herein wherein,

A₁ and A₂ are selected from C and N; wherein when A₁ is C, then A₂ is N;and wherein when A₂ is C, then A₁ is N;

R₁ is selected from —H, -halo, —OH, —C₁₋₂alkyl, —O—C₁₋₂alkyl, —NR₉R₁₀,—(C═O)—R₄, —CN, —NR₉—SO₂—R₄, and -Het₆; wherein each of said C₁₋₂alkylis optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, and —NR₁₁R₁₂;

R₇ is selected from —H, and -halo;

R₂ is selected from —H, —C₁₋₃alkyl, —(C═O)—NR₂₇R₂₈, —(C═O)-Het₃, and—SO₂—C₁₋₃alkyl; wherein each of said C₁₋₃alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from-halo, —OH, —O—CH₃, -Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₂alkyl, —(C═O)—C₁₋₂alkyl, —(C═O)-Het₂,—(C═O)—NR₂₉R₃₀, and —SO₂—C₁₋₂alkyl; wherein each of said C₁₋₂alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, —OH, and —O—CH₃;

R₄ is selected from —OH, —O—CH₃, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H —C₁₋₃alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₃alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —OCH₃, -Het₅, and —NR₃₁R₃₂;

R₆ is selected from —OH, and —NR₃₃R₃₄;

R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₃₁, R₃₂, R₃₃, and R₃₄ are eachindependently selected from —H and —CH₃;

R₁₇, R₁₈, R₂₇, and R₂₈ are each independently selected from —H and—C₁₋₂alkyl, each of said —C₁₋₂alkyl being optionally and independentlysubstituted with from 1 to 3 substituents selected from —OH,-halo-NR₃₅R₃₆ and -Het₇

R₂₉ and R₃₀, are each independently selected from —H, —OH and —OCH₃;

R₃₅ and R₃₆ are each independently selected from —H, —O, and C₁₋₆alkyl;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH,—O—C₁₋₆alkyl, and —S—C₁₋₆alkyl;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —(C═O)—, —S—C₁₋₆alkyl-,—NR₃—(C═O)—, —C₁₋₆alkyl-NR₃—(C═O)—, —NR₃—(C═O)—NR₃₅—, —NR₃—C₁₋₆alkyl-,and —NR₃—SO₂—C₁₋₆alkyl-;

X₂ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —(C═O)—NR₂—, and—NR₂—C₁₋₆alkyl-;

Y is selected from a direct bond, —CHR₆—, —O—, —S—, and —NR₅—;

Het₁ is selected from -piperidinyl and -piperazinyl; each of said Het₁being substituted with C₁₋₂alkyl; each of said C₁₋₂alkyl beingoptionally and independently substituted with from 1 to 3 -halo;

Het₂ is -piperidinyl-CH₃;

Het₃ is selected from -piperazinyl, and -morpholinyl;

Het₄, is selected from -piperazinyl, and -morpholinyl; each of said Het₄being optionally and independently substituted with C₁₋₂alkyl; each ofsaid C₁₋₂alkyl being optionally and independently substituted with from1 to 3 -halo;

Het₅ is -morpholinyl;

Het₆, is -piperazinyl;

Het₇ is -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N

m and n are each independently 1, 2, 3, or 4.

In yet a further embodiment, the present invention provides a compound adefined herein, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, than A₂ is N;and wherein when A₂ is C, than A₁ is N;

R₁ is selected from —H, -halo, —C₁₋₆alkyl, —OC₁₋₆alkyl, and —(C═O)—R₄;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 -halo;

R₇ is —H;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—O—C₁₋₆alkyl, and —(C═O)-Het₃;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from —OH,—OC₁₋₆alkyl, -Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₆alkyl, and —(C═O)-Het₂; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents —OH;

R₄ is selected from —OH, —O—C₁₋₆alkyl, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from —OH, and -Het₅;

R₁₃, R₁₄, R₁₇, R₁₈, R₁₉ and R₂₀ are each independently selected from —H,—O, —C₁₋₆alkyl, and Het₁;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —NR₃—(C═O)—,—C₁₋₆alkyl-NR₃—(C═O)—, and —NR₃—C₁₋₆alkyl-;

X₂ is selected from —O—C₁₋₆alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₆alkyl-;

Y is selected from a direct bond, —O—, —S—, and —NR₅—;

Het₁, Het₂, Het₃, Het₄ and Het₅ are each independently a 5- or6-membered monocyclic heterocycle having from 1 to 3 heteroatomsselected from O, N and S, wherein each heterocycle is being optionallysubstituted with from 1 to 3 —C₁₋₆alkyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N;

m and n are each independently 1, 2, 3, or 4.

In another specific embodiment, the present invention provides acompound as defined herein, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, than A₂ is N;and wherein when A₂ is C, than A₁ is N

R₁ is selected from —H, -halo, —CF₃, —OC₁₋₆alkyl, and —(C═O)—R₄;

R₇ is —H;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—O—C₁₋₆alkyl, and —(C═O)-Het₃;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from —OH,—OC₁₋₆alkyl, -Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₆alkyl, and —(C═O)-Het₂; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 —OH;

R₄ is selected from —OH, —OC₁₋₆alkyl, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from —OH, and -Het₅;

R₁₃ and R₁₄ are each independently selected from —H, and —C₁₋₆alkyl;

R₁₇ and R₁₈ are each independently selected from —H, —C₁₋₆alkyl, and-Het₁:

R₁₉ and R₂₀ are each independently selected from —O, and —C₁₋₆alkyl;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —NR₃—(C═O)—,—C₁₋₆alkyl-NR₃—(C═O)—, and —NR₃—C₁₋₆alkyl-;

X₂ is selected from —O—C₁₋₆alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₆alkyl-;

Y is selected from a direct bond, —O—, —S—, and —NR₅—;

Het₁, Het₂, Het₃, Het₄ and Het₅ are each independently selected from-morpholinyl, -piperidinyl, -piperazinyl, and pyrrolidinyl, wherein eachheterocycle is optionally substituted with from 1 to 3 —C₁₋₆alkyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N

m and n are each independently 1, 2, 3, or 4.

In yet a further embodiment, the present invention provides a compoundaccording to this invention, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, than A₂ is N;and wherein when A₂ is C, than A₁ is N

R₁ is selected from —H, -halo, —CF₃, —OCH₃, and —(C═O)—R₄;

R₇ is —H;

R₂ is selected from —H, —C₂₋₄alkyl, —(C═O)—O—C₂₋₄alkyl, and —(C═O)-Het₃;wherein each of said C₂₋₄alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from —OH, —OCH₃,-Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₂alkyl, and —(C═O)-Het₂; wherein each ofsaid C₁₋₂alkyl is optionally and independently substituted with from 1to 3 —OH;

R₄ is selected from —OH, —OCH₃, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H, —C₁₋₃alkyl, and —C₃₋₆cycloalkyl; wherein eachC₁₋₃alkyl is optionally substituted with from 1 to 3 substituentsselected from —OH, and -Het₅;

R₁₃ and R₁₄ are —CH₃;

R₁₇ and R₁₈ are each independently selected from —H, —CH₃, and -Het₁;

R₁₉ and R₂₀ are each —O;

X₁ is selected from —C₁₋₆alkyl-, —O—C₂₋₆alkyl-, —NR₃—(C═O)—,—C₁₋₆alkyl-NR₃—(C═O)—, and —NR₃—C₂₋₃alkyl-;

X₂ is selected from —O—C₂alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₃alkyl-;

Y is selected from a direct bond, —O—, —S—, and —NR₅—;

Het₁, Het₂, Het₃, Het₄ and Het₅ are each independently selected from-morpholinyl, -piperidinyl, -piperazinyl, and pyrrolidinyl, wherein eachheterocycle is optionally substituted with from 1 to 3 —CH₃;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N

m and n are each independently 1, 2, 3, or 4.

In a further specific embodiment, the invention provides a compound asdefined herein, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, than A₂ is N;and wherein when A₂ is C, than A₁ is N;

R₁ is selected from —H, -halo, —CF₃, —OCH₃, —(C═O)—OH, —(C═O)—OCH₃,—(C═O)-Het₄, —(C═O)—NH-Het₄, —(C═O)—NH₂, and —(C═O)—NH—CH₃;

R₇ is —H;

R₂ is selected from —H, —C₂₋₄alkyl, —(C═O)—O—C₂alkyl, and —(C═O)-Het₃;wherein each C₂₋₄alkyl is optionally and independently substituted with1 substituent selected from —OH, —OCH₃, -Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₂alkyl, and —(C═O)-Het₂; wherein saidC₁₋₂alkyl is optionally and independently substituted with 1 —OH;

R₅ is selected from —H, —C₁₋₃alkyl, and —C₃₋₆cycloalkyl; wherein eachC₁₋₃alkyl is optionally and independently substituted with 1 to 3substituents selected from —OH, and -Het₅;

R₁₃ and R₁₄ are —CH₃;

X₁ is selected from —C₁₋₆alkyl-, —O—C₂₋₆alkyl-, —NR₃—(C═O)—, and—NR₃—C₂alkyl-;

X₂ is selected from —O—C₂alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₃alkyl-;

Y is selected from a direct bond, —O—, —S—, and —NR₅—;

Ar₃ is phenyl substituted with —NO₂;

Het₂ is -piperidinyl substituted with —CH₃;

Het₃ is selected from -morpholinyl, and -piperazinyl;

Het₄ is selected from -morpholinyl, -piperidinyl, and -piperazinyl;wherein said -piperidinyl and -piperazinyl are substituted with —CH₃;

Het₅ is selected from -morpholinyl, and -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N

m and n are each independently 1, 2, 3, or 4.

The invention further provides a compound as defined herein, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, then A₂ is N;and wherein when A₂ is C, then A₁ is N;

R₁ and R₇ are each independently selected from —H, -halo, —C₁₋₆alkyl,—O—C₁₋₆alkyl, and —(C═O)—R₄; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, and —OH;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈, and —(C═O)-Het₃;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH, and—NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₆alkyl, and —(C═O)-Het₂; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with —OH;

R₄ is independently selected from —OH, and —NR₁₇R₁₈;

R₅ is selected from —H —C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —OC₁₋₆alkyl, -Het₅, and—NR₃₁R₃₂;

R₁₃, R₁₄, R₁₇, R₁₈, R₂₇, R₂₈, R₃₁, R₃₂ are each independently selectedfrom —H, and —C₁₋₆alkyl; wherein each of said C₁₋₆alkyl is optionallyand independently substituted with from 1 to 3 substituents selectedfrom -halo, —NR₃₅R₃₆, and -Het₇;

R₃₅ and R₃₆ are each —C₁₋₆alkyl;

X₁ is selected from —O—C₁₋₆alkyl-, —(C═O)—, —NR₃—(C═O)—,C₁₋₆alkyl-NR₃—(C═O)—; and —NR₃—;

X₂ is selected from —O—C₁₋₆alkyl-, and —NR₂—;

Y is selected from a direct bond, —O—, and —NR₅—;

Het₃ is -piperazinyl

Het₂ is -piperidinyl substituted with —CH₃;

Het₅ is selected from -morpholinyl and -pyrrolidinyl;

Het₇ is -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N;

m and n are each independently 1, 2, 3, or 4.

In a preferred embodiment, the present invention provides a compound asdefined herein, wherein

A₁ is N; and A₂ is C;

R₁ and R₇ are each independently selected from —H, —C₁₋₆alkyl,—O—C₁₋₆alkyl, and —(C═O)—R₄; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, and —OH;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from —OH;

R₃ and R₃₅ are each independently selected from —H, —C₁₋₆alkyl, and—(C═O)-Het₂; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with —OH;

R₄ is independently selected from —OH, and —NR₁₇R₁₈;

R₅ is selected from —H —C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —OC₁₋₆alkyl, and -Het₅;

R₁₇, R₁₈, R₂₇, and R₂₈ are each independently selected from —H, and—C₁₋₆alkyl; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from—NR₃₅R₃₆, and -Het₇;

R₃₅ and R₃₆ are each —C₁₋₆alkyl;

X₁ is selected from —O—C₁₋₆alkyl-, —NR₃—(C═O)—, and —NR₃—;

X₂ is selected from —O—C₁₋₆alkyl-, and —NR₂—;

Y is selected from a direct bond, —O—, and —NR₅—;

Het₂ is -piperidinyl substituted with —CH₃;

Het₅ is selected from -morpholinyl and -pyrrolidinyl;

Het₇ is -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each C;

m and n are each independently 1, 2, 3, or 4.

In another preferred embodiment, the present invention provides acompound as defined herein, wherein

A₁ is N; and A₂ is C;

R₁ and R₇ are each —H;

R₂ is selected from —H, —(C═O)—NR₂₇R₂₈ and —C₁₋₆alkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 —OH;

R₅ is selected from —H and —C₁₋₆alkyl; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 -Het₅;

R₂₇, and R₂₈ are each independently selected from —H, and —C₁₋₆alkyl;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from —NR₃₅R₃₆, and-Het₇;

R₃₅ and R₃₆ are each —C₁₋₆alkyl;

X₁ is selected from —O—CH₂—;

X₂ is selected from —O—CH₂—, and —NR₂—;

Y is —NR₅—;

Het₅ is selected from -morpholinyl and -pyrrolidinyl;

Het₇ is -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each C;

m is 1; and

n is selected from 1, 2 and 3.

Particularly interesting compounds of the invention are compoundsaccording to formula (I) wherein one or more of the following applies:

A₁ and A₂ are selected from C and N; wherein when A₁ is C, then A₂ is N;and wherein when A₂ is C, then A₁ is N;

R₁ and R₇ are each independently selected from —H, -halo, —C₁₋₆alkyl,—O—C₁₋₆alkyl, and —(C═O)—R₄; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, and —OH;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈, and —(C═O)-Het₃;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH, and—NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₆alkyl, and —(C═O)-Het₂; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with —OH;

R₄ is independently selected from —OH, and —NR₁₇R₁₈;

R₅ is selected from —H —C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —OC₁₋₆alkyl, -Het₅, and—NR₃₁R₃₂;

R₁₃, R₁₄, R₁₇, R₁₈, R₂₇, R₂₈, R₃₁, R₃₂ are each independently selectedfrom —H, and —C₁₋₆alkyl; wherein each of said C₁₋₆alkyl is optionallyand independently substituted with from 1 to 3 substituents selectedfrom -halo, —NR₃₅R₃₆, and -Het₇;

R₃₅ and R₃₆ are each —C₁₋₆alkyl;

X₁ is selected from —O—C₁₋₆alkyl-, —(C═O)—, —NR₃—(C═O)—,C₁₋₆alkyl-NR₃—(C═O)—; and —NR₃—;

X₂ is selected from —O—C₁₋₆alkyl-, and —NR₂—;

Y is selected from a direct bond, —O—, and —NR₅—;

Het₃ is -piperazinyl

Het₂ is -piperidinyl substituted with —CH₃;

Het₅ is selected from -morpholinyl and -pyrrolidinyl;

Het₇ is -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N;

m and n are each independently 1, 2, 3, or 4.

Further particularly interesting compounds of the invention arecompounds according to formula (I) wherein one or more of the followingapplies:

A₁ is N; and A₂ is C;

R₁ is selected from —H, -halo, —C₁₋₆alkyl, —(C═O)—R₄, and —O—C₁₋₆alkyl,wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, and —OH;

R₇ is —H;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈, and —(C═O)-Het₃;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH, and—NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₆alkyl, and —(C═O)-Het₂; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 —OH;

R₄ is independently selected from —OH and —NH₁₇R₁₈;

R₅ is selected from —H —C₁₋₆alkyl, —C₃₋₆cycloalkyl; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —OC₁₋₆alkyl, -Het₅, and —NR₃₁R₃₂;

R₁₃ and R₁₄ are each —C₁₋₆alkyl;

R₁₇ and R₁₈ are each independently selected from —H, and —C₁₋₆alkyl;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo,

R₂₇, and R₂₈ are each independently selected from —H and —C₁₋₆alkyl;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —NR₃₅R₃₆,and -Het₇;

R₃₁ and R₃₂ are each —C₁₋₆alkyl;

R₃₅ and R₃₆ are each —C₁₋₆alkyl

X₁ is selected from —O—C₁₋₆alkyl-, —NR₃—(C═O)—, —NR₃—C₁₋₆alkyl-;

X₂ is selected from —O—C₁₋₆alkyl-, and —NR₂

Y is selected from —O— and —NR₅—;

Het₃ is -piperazinyl

Het₂ is -piperidinyl substituted with —CH₃;

Het₅ is selected from -morpholinyl and -pyrrolidinyl;

Het₇ is -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N;

m and n are each independently 1, 2, 3, or 4.

In another particular embodiment, the present invention providescompounds of Formula I, wherein one or more of the following applies:

A₁ is N; and A₂ is C;

R₁ and R₇ are each —H;

R₂ is selected from —H, —(C═O)—NR₂₇R₂₈ and —C₁₋₆alkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 —OH;

R₅ is selected from —H and —C₁₋₆alkyl; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 -Het₅;

R₂₇, and R₂₈ are each independently selected from —H, and —C₁₋₆alkyl;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from —NR₃₅R₃₆, and-Het₇;

R₃₅ and R₃₆ are each —C₁₋₆alkyl;

X₁ is selected from —O—CH₂—;

X₂ is selected from —O—CH₂—, and —NR₂—;

Y is —NR₅—;

Het₅ is selected from -morpholinyl and -pyrrolidinyl;

Het₇ is -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each C;

m is 1; and

n is selected from 1, 2 and 3.

In particular the present invention provides a compound, or astereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt,hydrate, N-oxide form, or solvate thereof, selected from the listcomprising:

More in particular the present invention provides a compound selectedfrom the list comprising:

more in particular

In a preferred embodiment, the present invention provides a compound asdefined herein above, wherein the pyrazolopyrimidine moiety is linked tothe aryl or heteroaryl moiety at position Z₄ and wherein R₇ is linked tothe aryl or heteroaryl moiety at position Z₅ in accordance with FormulaI.

The compounds of the present invention can be prepared according to thereaction schemes provided in the examples hereinafter, but those skilledin the art will appreciate that these are only illustrative for theinvention and that the compounds of this invention can be prepared byany of several standard synthetic processes commonly used by thoseskilled in the art of organic chemistry.

In a preferred embodiment, the present invention provides a compound asdefined herein above, wherein the pyrazolopyrimidine moiety is linked tothe aryl or heteroaryl moiety at position Z₄ and wherein R₇ is linked tothe aryl or heteroaryl moiety at position Z₅ in accordance with FormulaI.

In a further aspect, the present invention provides a compound accordingto this invention for use as a human or veterinary medicine. More inparticular, it provides the use of a compound according to thisinvention for the manufacture of a medicament for the treatment of cellproliferative disorders, such as cancer.

The present invention further provides a pharmaceutical compositioncomprising a compound according to this invention, suitable for use as ahuman or veterinary medicine.

In yet a further aspect, the present invention provides the use of acompound or a composition according to this invention, suitable forinhibiting the activity of a kinase; in particular a FLT3 kinase.

It further provides the use of a compound or a composition according tothis invention for the prevention and/or or treatment of cellproliferative disorders, such as cancer.

In a further aspect, the present invention provides a method for theprevention and/or treatment of cell proliferative disorders such ascancer; said method comprising administering to a subject in needthereof a compound or a composition according to this invention.

Further embodiments of the present invention are detailed herein belowin the form of numbered statements:

1. A compound of Formula I or a stereoisomer, tautomer, racemic,metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvatethereof,

Wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, then A₂ is N;and wherein when A₂ is C, then A₁ is N;

R₁ and R₇ are each independently selected from —H, -halo, —OH,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —NR₉R₁₀, —(C═O)—R₄, —SO₂—R₄,—CN, —NR₉—SO₂—R₄, —C₃₋₆cycloalkyl, and -Het₆; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —NR₁₁R₁₂, —O—C₁₋₆alkyl, and—S—C₁₋₆alkyl;

R₂ is selected from —H, -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)—O—C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈,-Het₃, —(C═O)-Het₃, —SO₂—C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,-Het₂, —Ar₂, and —NR₁₃R₁₄;

R₃ and R₃₅ are each independently selected from —H, -halo, —OH,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl,—(C═O)—O—C₁₋₆alkyl, -Het₂, —C₃₋₆cycloalkyl-(C═O)-Het₂, —(C═O)—NR₂₉R₃₀,and —SO₂—C₁₋₆alkyl; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from-halo, —OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —NR₁₅R₁₆, -Het₂, and —Ar₃;

R₄ is independently selected from -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H —C₁₋₆alkyl, —C₃₋₆cycloalkyl; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —OC₁₋₆alkyl, —SC₁₋₆alkyl, -Het₅,and —NR₃₁R₃₂;

R₆ is selected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₃₃R₃₄, and -Het₈;

R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄ are eachindependently selected from —H, —O, —C₁₋₆alkyl, and Het₁; wherein eachof said C₁₋₆alkyl is optionally and independently substituted with from1 to 3 substituents selected from -halo, —OH, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₃₅R₃₆, -Het₇, and —Ar₄;

R₃₅ and R₃₆ are each independently selected from —H, —O, and C₁₋₆alkyl;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH,—O—C₁₋₆alkyl, and —S—C₁₋₆alkyl;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-, —(C═O)—,—NR₃—(C═O)—, —NR₃—(C═O)—NR₃₅—, —NR₃—C₁₋₆alkyl-, —NR₃—, and —NR₃—SO₂—;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, and —NR₂₃R₂₄;

X₂ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-, —(C═O)—,—NR₂—(C═O)—, —NR₂—C₁₋₆alkyl-, —NR₂—, and —SO₂—NR₂—; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, and —NR₂₅R₂₆;

Y is selected from a direct bond, —CHR₆—, —O—, —S—, and —NR₅—;

Ar₂, Ar₃, and Ar₄ are each independently a 5- or 6-membered aromaticheterocycle optionally comprising 1 or 2 heteroatoms selected from O, Nand S; wherein each of said Ar₂, Ar₃, and Ar₄ is optionally andindependently substituted with from 1 to 3 substituents selected from—NR₁₉R₂₀, —C₁₋₆alkyl, —O—C₁₋₆alkyl, and —S—C₁₋₆alkyl;

Het₁, Het₂, Het₃, Het₄, Het₅, Het₆, Het₇ and Het₈ are each independentlya 5- or 6-membered monocyclic heterocycle having from 1 to 3 heteroatomsselected from O, N and S, wherein each heterocycle is optionallysubstituted with from 1 to 3 substituents selected from —C₁₋₆alkyl,—OC₁₋₆alkyl, —SC₁₋₆alkyl, and —NR₂₁R₂₂; wherein each of said C₁₋₆alkylis optionally and independently substituted with from 1 to 3 -halo;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N;

m and n are each independently 1, 2, 3, or 4.

2. A compound as defined in statement 1, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, then A₂ is N;and wherein when A₂ is C, then A₁ is N;

R₁ is selected from —H, -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —NR₉R₁₀,—(C═O)—R₄, —CN, —NR₉—SO₂—R₄, and -Het₆; wherein each of said C₁₋₆alkylis optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, and —NR₁₁R₁₂;

R₇ is selected from —H, and -halo;

R₂ is selected from —H, —C₁₋₆alkyl, (C═O)—NR₂₇R₂₈, —(C═O)-Het₃, and—SO₂—C₁₋₆alkyl; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from-halo, —OH, —O—C₁₋₆alkyl, -Het₃, and —NR₁₃R₁₄;

R₃ and R₃₅ are each independently selected from —H, —C₁₋₆alkyl,—(C═O)—C₁₋₆alkyl, —(C═O)-Het₂, —(C═O)—NR₂₉R₃₀, and —SO₂—C₁₋₆alkyl;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH, and—O—C₁₋₆alkyl;

R₄ is independently selected from —OH, —O—C₁₋₆alkyl, —NR₁₇R₁₈, and-Het₄;

R₅ is selected from —H, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —OC₁₋₆alkyl, -Het₅, and—NR₃₁R₃₂;

R₆ is selected from —OH, and —NR₃₃R₃₄;

R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₇, R₁₈, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂,R₃₃, R₃₄ are each independently selected from —H, —C₁₋₆alkyl, or Het₁;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH, and-Het₇;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-,—NR₃—(C═O)—, —NR₃—(C═O)—NR₃₅—, —NR₃—C₁₋₆alkyl-, and —NR₃—SO₂—;

X₂ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —(C═O)—NR₂—, and—NR₂—C₁₋₆alkyl-;

Y is selected from a direct bond, —CHR₆—, —O—, —S—, and —NR₅—;

Het₁, Het₂, Het₃, Het₄, Het₅, Het₆, and Het₇ are each independently a 5-or 6-membered monocyclic heterocycle having from 1 to 3 heteroatomsselected from O, N and S, wherein each heterocycle is being optionallysubstituted with from 1 to 3 —C₁₋₆alkyl; each of said C₁₋₆alkyl beingoptionally and independently substituted with from 1 to 3 -halo

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N;

m and n are each independently 1, 2, 3, or 4.

3. A compound as defined in statement 1, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, then A₂ is N;and wherein when A₂ is C, then A₁ is N;

R₁ is selected from —H, -halo, —OH, —C₁₋₂alkyl, —O—C₁₋₂alkyl, —NR₉R₁₀,—(C═O)—R₄, —CN, —NR₉—SO₂—R₄, and -Het₆; wherein each of said C₁₋₂alkylis optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, and —NR₁₁R₁₂;

R₇ is selected from —H, and -halo;

R₂ is selected from —H, —C₁₋₃alkyl, —(C═O)—NR₂₇R₂₈, —(C═O)-Het₃, and—SO₂—C₁₋₃alkyl; wherein each of said C₁₋₃alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from-halo, —OH, —O—CH₃, -Het₃, and —NR₁₃R₁₄;

R₃ and R₃₅ are each independently selected from —H, —C₁₋₂alkyl,—(C═O)—C₁₋₂alkyl, —(C═O)-Het₂, —(C═O)—NR₂₉R₃₀, and —SO₂—C₁₋₂alkyl;wherein each of said C₁₋₂alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH, and—O—CH₃;

R₄ is selected from —OH, —O—CH₃, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H —C₁₋₃alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₃alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —OCH₃, -Het₅, and —NR₃₁R₃₂;

R₆ is selected from —OH, and —NR₃₃R₃₄;

R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₃₁, R₃₂, R₃₃, and R₃₄ are eachindependently selected from —H and —CH₃;

R₁₇, R₁₈, R₂₇, and R₂₈ are each independently selected from —H and—C₁₋₂alkyl, each of said —C₁₋₂alkyl being optionally and independentlysubstituted with from 1 to 3 substituents selected from —OH, -halo and-Het₇

R₂₉ and R₃₀, are each independently selected from —H, —OH and —OCH₃;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-,—NR₃—(C═O)—, —NR₃—(C═O)—NR₃₅—, —NR₃—C₁₋₆alkyl-, and —NR₃—SO₂—C₁₋₆alkyl-;

X₂ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —(C═O)—NR₂—, and—NR₂—C₁₋₆alkyl-;

Y is selected from a direct bond, —CHR₆—, —O—, —S—, and —NR₅—;

Het₁ is selected from -piperidinyl and -piperazinyl; each of said Het₁being substituted with C₁₋₂alkyl; each of said C₁₋₂alkyl beingoptionally and independently substituted with from 1 to 3 -halo;

Het₂ is -piperidinyl-CH₃;

Het₃ is selected from -piperazinyl, and -morpholinyl;

Het₄, is selected from -piperazinyl, and -morpholinyl; each of said Het₄being optionally and independently substituted with C₁₋₂alkyl; each ofsaid C₁₋₂alkyl being optionally and independently substituted with from1 to 3 -halo;

Het₅ is -morpholinyl;

Het₆, is -piperazinyl;

Het₇ is -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N

m and n are each independently 1, 2, 3, or 4.

4. A compound as defined in statement 1, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, than A₂ is N;and wherein when A₂ is C, than A₁ is N;

R₁ is selected from —H, -halo, —C₁₋₆alkyl, —OC₁₋₆alkyl, and —(C═O)—R₄;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 -halo;

R₇ is —H;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—O—C₁₋₆alkyl, and —(C═O)-Het₃;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from —OH,—OC₁₋₆alkyl, -Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₆alkyl, and —(C═O)-Het₂; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents —OH;

R₄ is selected from —OH, —O—C₁₋₆alkyl, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from —OH, and -Het₅;

R₁₃, R₁₄, R₁₇, R₁₈, R₁₉ and R₂₀ are each independently selected from —H,—O, —C₁₋₆alkyl, and Het₁;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —NR₃—(C═O)—, and—NR₃—C₁₋₆alkyl-;

X₂ is selected from —O—C₁₋₆alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₆alkyl-;

Y is selected from a direct bond, —O—, —S—, and —NR₅—;

Het₁, Het₂, Het₃, Het₄ and Het₅ are each independently a 5- or6-membered monocyclic heterocycle having from 1 to 3 heteroatomsselected from O, N and S, wherein each heterocycle is being optionallysubstituted with from 1 to 3 —C₁₋₆alkyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N;

m and n are each independently 1, 2, 3, or 4.

5. A compound as defined in statement 1, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, than A₂ is N;and wherein when A₂ is C, than A₁ is N

R₁ is selected from —H, -halo, —CF₃, —OC₁₋₆alkyl, and —(C═O)—R₄;

R₇ is —H;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—O—C₁₋₆alkyl, and —(C═O)-Het₃;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from —OH,—OC₁₋₆alkyl, -Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₆alkyl, and —(C═O)-Het₂; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 —OH;

R₄ is selected from —OH, —OC₁₋₆alkyl, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from —OH, and -Het₅;

R₁₃ and R₁₄ are each independently selected from —H, and —C₁₋₆alkyl;

R₁₇ and R₁₈ are each independently selected from —H, —C₁₋₆alkyl, and-Het₁:

R₁₉ and R₂₀ are each independently selected from —O, and —C₁₋₆alkyl;

X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —NR₃—(C═O)—, and—NR₃—C₁₋₆alkyl-;

X₂ is selected from —O—C₁₋₆alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₆alkyl-;

Y is selected from a direct bond, —O—, —S—, and —NR₅—;

Het₁, Het₂, Het₃, Het₄ and Het₅ are each independently selected from-morpholinyl, -piperidinyl, -piperazinyl, and pyrrolidinyl, wherein eachheterocycle is optionally substituted with from 1 to 3 —C₁₋₆alkyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N

m and n are each independently 1, 2, 3, or 4.

6. A compound as defined in statement 1, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, than A₂ is N;and wherein when A₂ is C, than A₁ is N

R₁ is selected from —H, -halo, —CF₃, —OCH₃, and —(C═O)—R₄;

R₇ is —H;

R₂ is selected from —H, —C₂₋₄alkyl, —(C═O)—O—C₂₋₄alkyl, and —(C═O)-Het₃;wherein each of said C₂₋₄alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from —OH, —OCH₃,-Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₂alkyl, and —(C═O)-Het₂; wherein each ofsaid C₁₋₂alkyl is optionally and independently substituted with from 1to 3 —OH;

R₄ is selected from —OH, —OCH₃, —NR₁₇R₁₈, and -Het₄;

R₅ is selected from —H, —C₁₋₃alkyl, and —C₃₋₆cycloalkyl; wherein eachC₁₋₃alkyl is optionally substituted with from 1 to 3 substituentsselected from —OH, and -Het₅;

R₁₃ and R₁₄ are —CH₃;

R₁₇ and R₁₈ are each independently selected from —H, —CH₃, and -Het₁;

R₁₉ and R₂₀ are each —O;

X₁ is selected from —C₁₋₆alkyl-, —O—C₂₋₆alkyl-, —NR₃—(C═O)—, and—NR₃—C₂₋₃alkyl-;

X₂ is selected from —O—C₂alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₃alkyl-;

Y is selected from a direct bond, —O—, —S—, and —NR₅—;

Het₁, Het₂, Het₃, Het₄ and Het₅ are each independently selected from-morpholinyl, -piperidinyl, -piperazinyl, and pyrrolidinyl, wherein eachheterocycle is optionally substituted with from 1 to 3 —CH₃;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N

m and n are each independently 1, 2, 3, or 4.

7. A compound as defined in statement 1, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, than A₂ is N;and wherein when A₂ is C, than A₁ is N;

R₁ is selected from —H, -halo, —CF₃, —OCH₃, —(C═O)—OH, —(C═O)—OCH₃,—(C═O)-Het₄, —(C═O)—NH-Het₄, —(C═O)—NH₂, and —(C═O)—NH—CH₃;

R₇ is —H;

R₂ is selected from —H, —C₂₋₄alkyl, —(C═O)—O—C₂alkyl, and —(C═O)-Het₃;wherein each C₂₋₄alkyl is optionally and independently substituted with1 substituent selected from —OH, —OCH₃, -Het₃, and —NR₁₃R₁₄;

R₃ is selected from —H, —C₁₋₂alkyl, and —(C═O)-Het₂; wherein saidC₁₋₂alkyl is optionally and independently substituted with 1 —OH;

R₅ is selected from —H, —C₁₋₃alkyl, and —C₃₋₆cycloalkyl; wherein eachC₁₋₃alkyl is optionally and independently substituted with 1 to 3substituents selected from —OH, and -Het₅;

R₁₃ and R₁₄ are —CH₃;

X₁ is selected from —C₁₋₆alkyl-, —O—C₂₋₆alkyl-, —NR₃—(C═O)—, and—NR₃—C₂alkyl-;

X₂ is selected from —O—C₂alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₃alkyl-;

Y is selected from a direct bond, —O—, —S—, and —NR₅—;

Ar₃ is phenyl substituted with —NO₂;

Het₂ is -piperidinyl substituted with —CH₃;

Het₃ is selected from -morpholinyl, and -piperazinyl;

Het₄ is selected from -morpholinyl, -piperidinyl, and -piperazinyl;wherein said -piperidinyl and -piperazinyl are substituted with —CH₃;

Het₅ is selected from -morpholinyl, and -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N

m and n are each independently 1, 2, 3, or 4.

8. A compound as defined in statement 1, wherein

A₁ and A₂ are selected from C and N; wherein when A₁ is C, then A₂ is N;and wherein when A₂ is C, then A₁ is N;

R₁ and R₇ are each independently selected from —H, -halo, —C₁₋₆alkyl,—O—C₁₋₆alkyl, and —(C═O)—R₄; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, and —OH;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈, and —(C═O)-Het₃;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH, and—NR₁₃R₁₄;

R₃ and R₃₅ are each independently selected from —H, —C₁₋₆alkyl, and—(C═O)-Het₂; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with —OH;

R₄ is independently selected from —OH, and —NR₁₇R₁₈;

R₅ is selected from —H —C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —OC₁₋₆alkyl, -Het₅, and—NR₃₁R₃₂;

R₁₃, R₁₄, R₁₇, R₁₈, R₂₇, R₂₈, R₃₁, R₃₂ are each independently selectedfrom —H, and —C₁₋₆alkyl; wherein each of said C₁₋₆alkyl is optionallyand independently substituted with from 1 to 3 substituents selectedfrom -halo, —NR₃₅R₃₆, and -Het₇;

R₃₅ and R₃₆ are each —C₁₋₆alkyl;

X₁ is selected from —O—C₁₋₆alkyl-, —NR₃—(C═O)—, and —NR₃—;

X₂ is selected from —O—C₁₋₆alkyl-, and —NR₂—;

Y is selected from a direct bond, —O—, and —NR₅—;

Het₃ is -piperazinyl

Het₂ is -piperidinyl substituted with —CH₃;

Het₅ is selected from -morpholinyl and -pyrrolidinyl;

Het₇ is -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N;

m and n are each independently 1, 2, 3, or 4.

9. A compound as defined in statement 1, wherein

A₁ is N; and A₂ is C;

R₁ and R₇ are each independently selected from —H, —C₁₋₆alkyl,—O—C₁₋₆alkyl, and —(C═O)—R₄; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, and —OH;

R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from —OH;

R₃ and R₃₅ are each independently selected from —H, —C₁₋₆alkyl, and—(C═O)-Het₂; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with —OH;

R₄ is independently selected from —OH, and —NR₁₇R₁₈;

R₅ is selected from —H —C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —OC₁₋₆alkyl, and -Het₅;

R₁₇, R₁₈, R₂₇, and R₂₈ are each independently selected from —H, and—C₁₋₆alkyl; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from—NR₃₅R₃₆, and -Het₇;

R₃₅ and R₃₆ are each —C₁₋₆alkyl;

X₁ is selected from —O—C₁₋₆alkyl-, —NR₃—(C═O)—, and —NR₃—;

X₂ is selected from —O—C₁₋₆alkyl-, and —NR₂—;

Y is selected from a direct bond, —O—, and —NR₅—;

Het₂ is -piperidinyl substituted with —CH₃;

Het₅ is selected from -morpholinyl and -pyrrolidinyl;

Het₇ is -pyrrolidinyl;

Z₁, Z₂, Z₃, Z₄ and Z₅ are each C;

m and n are each independently 1, 2, 3, or 4.

10. A compound as defined in any one of statements 1 to 9 wherein thepyrazolopyrimidine moiety is linked to the aryl or heteroaryl moiety atposition Z₄ and wherein R₇ is linked to the aryl or heteroaryl moiety atposition Z₅ in accordance with Formula I.

11. A compound as defined in any one of statements 1 to 10, for use as ahuman or veterinary medicine.

12. Use of a compound as defined in any one of statements 1 to 10 in themanufacture of a medicament for the treatment of cell proliferativedisorders, such as cancer.

13. A pharmaceutical composition comprising a compound as defined in anyone of statements 1 to 10, suitable for use as a human or veterinarymedicine.

14. Use of a compound as defined in any one of statements 1 to 10, or acomposition as defined in statement 13, suitable for inhibiting theactivity of a kinase; in particular a FLT3 kinase.

15. Use of a compound as defined in any one of statements 1 to 10, or acomposition as defined in statement 13, for the prevention and/ortreatment of cell proliferative disorders, such as cancer.

16. A method for the prevention and/or treatment of cell proliferativedisorders such as cancer; said method comprising administering to asubject in need thereof a compound according to any one of statements 1to 9 or a composition as defined in statement 13.

Method of Treatment

Compounds of formula (I) a stereoisomer, tautomer, racemic, metabolite,pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, areinhibitors of FLT3 kinase activity and are thus believed to be ofpotential use in the treatment of hematological malignancies includeleukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (alsocalled Hodgkin's lymphoma), and myeloma—for instance, acute lymphocyticleukemia (ALL), acute myeloid leukemia (AML), acute promyelocyticleukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), chronic neutrophilic leukemia (CNL), acuteundifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL),prolymphocytic leukemia (PML), juvenile myelomonocyctic leukemia (JMML),adult T-cell ALL, AML with trilineage myelodysplasia (AML/TMDS), mixedlineage leukemia (MLL), myelodysplastic syndromes (MDSs),myeloproliferative disorders (MPD), multiple myeloma, (MM) and myeloidsarcoma. The methods of the present invention can be utilized in avariety of settings, including, for example, in selecting the optimaltreatment course for a patient, in predicting the likelihood of successwhen treating an individual patient with a particular treatment regimen,in assessing disease progression, in monitoring treatment efficacy, indetermining prognosis for individual patients and in assessingpredisposition of an individual to benefit from a particular therapy.

In the invention, particular preference is given to compounds of FormulaI or any subgroup thereof that in the inhibition assay for FLT3described below inhibit kinase activity with an IC₅₀ value of less than10 μM, preferably less than 1 μM, most preferably less than 100 nM.

Said inhibition may be effected in vitro and/or in vivo, and wheneffected in vivo, is preferably effected in a selective manner, asdefined above.

The term “FLT3 kinase-mediated condition” or “disease”, as used herein,means any disease or other deleterious condition in which the FLT3kinase is known to play a role. The term “FLT3 kinase-mediatedcondition” or “disease” also means those diseases or conditions that arealleviated by treatment with a FLT3 kinase inhibitor. Accordingly,another embodiment of the present invention relates to treating orlessening the severity of one or more diseases in which the FLT3 kinaseis known to play a role.

For pharmaceutical use, the compounds of the invention may be used as afree acid or base, and/or in the form of a pharmaceutically acceptableacid-addition and/or base-addition salt (e.g. obtained with non-toxicorganic or inorganic acid or base), in the form of a hydrate, solvateand/or complex, and/or in the form or a pro-drug or pre-drug, such as anester. As used herein and unless otherwise stated, the term “solvate”includes any combination which may be formed by a compound of thisinvention with a suitable inorganic solvent (e.g. hydrates) or organicsolvent, such as but not limited to alcohols, ketones, esters and thelike. Such salts, hydrates, solvates, etc. and the preparation thereofwill be clear to the skilled person; reference is for instance made tothe salts, hydrates, solvates, etc. described in U.S. Pat. Nos.6,372,778, 6,369,086, 6,369,087 and U.S. Pat. No. 6,372,733.

The pharmaceutically acceptable salts of the compounds according to theinvention, i.e. in the form of water-, oil-soluble, or dispersibleproducts, include the conventional non-toxic salts or the quaternaryammonium salts which are formed, e.g., from inorganic or organic acidsor bases. Examples of such acid addition salts include acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate,palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.Base salts include ammonium salts, alkali metal salts such as sodium andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth. In addition, the basicnitrogen-containing groups may be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl;and diamyl sulfates, long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl-bromides and others. Other pharmaceutically acceptablesalts include the sulfate salt ethanolate and sulfate salts.

Generally, for pharmaceutical use, the compounds of the inventions maybe formulated as a pharmaceutical preparation or pharmaceuticalcomposition comprising at least one compound of the invention and atleast one pharmaceutically acceptable carrier, diluent or excipientand/or adjuvant, and optionally one or more further pharmaceuticallyactive compounds.

By means of non-limiting examples, such a formulation may be in a formsuitable for oral administration, for parenteral administration (such asby intravenous, intramuscular or subcutaneous injection or intravenousinfusion), for administration by inhalation, by a skin patch, by animplant, by a suppository, etc. Such suitable administration forms—whichmay be solid, semi-solid or liquid, depending on the manner ofadministration—as well as methods and carriers, diluents and excipientsfor use in the preparation thereof, will be clear to the skilled person;reference is again made to for instance U.S. Pat. Nos. 6,372,778,6,369,086, 6,369,087 and U.S. Pat. No. 6,372,733, as well as to thestandard handbooks, such as the latest edition of Remington'sPharmaceutical Sciences.

Some preferred, but non-limiting examples of such preparations includetablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols, ointments, creams,lotions, soft and hard gelatin capsules, suppositories, eye drops,sterile injectable solutions and sterile packaged powders (which areusually reconstituted prior to use) for administration as a bolus and/orfor continuous administration, which may be formulated with carriers,excipients, and diluents that are suitable per se for such formulations,such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gumacacia, calcium phosphate, alginates, tragacanth, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethyleneglycol, cellulose, (sterile) water, methylcellulose, methyl- andpropylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetableoils and mineral oils or suitable mixtures thereof. The formulations canoptionally contain other pharmaceutically active substances (which mayor may not lead to a synergistic effect with the compounds of theinvention) and other substances that are commonly used in pharmaceuticalformulations, such as lubricating agents, wetting agents, emulsifyingand suspending agents, dispersing agents, desintegrants, bulking agents,fillers, preserving agents, sweetening agents, flavoring agents, flowregulators, release agents, etc. The compositions may also be formulatedso as to provide rapid, sustained or delayed release of the activecompound(s) contained therein, for example using liposomes orhydrophilic polymeric matrices based on natural gels or syntheticpolymers. In order to enhance the solubility and/or the stability of thecompounds of a pharmaceutical composition according to the invention, itcan be advantageous to employ α-, β- or γ-cyclodextrins or theirderivatives. An interesting way of formulating the compounds incombination with a cyclodextrin or a derivative thereof has beendescribed in EP-A-721,331. In particular, the present inventionencompasses a pharmaceutical composition comprising an effective amountof a compound according to the invention with a pharmaceuticallyacceptable cyclodextrin.

In addition, co-solvents such as alcohols may improve the solubilityand/or the stability of the compounds. In the preparation of aqueouscompositions, addition of salts of the compounds of the invention can bemore suitable due to their increased water solubility.

For local administration, the compounds may advantageously be used inthe form of a spray, ointment or transdermal patch or another suitableform for topical, transdermal and/or intradermal administration.

More in particular, the compositions may be formulated in apharmaceutical formulation comprising a therapeutically effective amountof particles consisting of a solid dispersion of the compounds of theinvention and one or more pharmaceutically acceptable water-solublepolymers.

The term “a solid dispersion” defines a system in a solid state (asopposed to a liquid or gaseous state) comprising at least twocomponents, wherein one component is dispersed more or less evenlythroughout the other component or components. When said dispersion ofthe components is such that the system is chemically and physicallyuniform or homogenous throughout or consists of one phase as defined inthermodynamics, such a solid dispersion is referred to as “a solidsolution”. Solid solutions are preferred physical systems because thecomponents therein are usually readily bioavailable to the organisms towhich they are administered.

It may further be convenient to formulate the compounds in the form ofnanoparticles which have a surface modifier adsorbed on the surfacethereof in an amount sufficient to maintain an effective averageparticle size of less than 1000 nm. Suitable surface modifiers canpreferably be selected from known organic and inorganic pharmaceuticalexcipients. Such excipients include various polymers, low molecularweight oligomers, natural products and surfactants. Preferred surfacemodifiers include nonionic and anionic surfactants.

Yet another interesting way of formulating the compounds according tothe invention involves a pharmaceutical composition whereby thecompounds are incorporated in hydrophilic polymers and applying thismixture as a coat film over many small beads, thus yielding acomposition with good bio-availability which can conveniently bemanufactured and which is suitable for preparing pharmaceutical dosageforms for oral administration. Materials suitable for use as cores inthe beads are manifold, provided that said materials arepharmaceutically acceptable and have appropriate dimensions andfirmness. Examples of such materials are polymers, inorganic substances,organic substances, and saccharides and derivatives thereof.

The preparations may be prepared in a manner known per se, which usuallyinvolves mixing at least one compound according to the invention withthe one or more pharmaceutically acceptable carriers, and, if desired,in combination with other pharmaceutical active compounds, whennecessary under aseptic conditions. Reference is again made to U.S. Pat.Nos. 6,372,778, 6,369,086, 6,369,087 and U.S. Pat. No. 6,372,733 and thefurther prior art mentioned above, as well as to the standard handbooks,such as the latest edition of Remington's Pharmaceutical Sciences.

The pharmaceutical preparations of the invention are preferably in aunit dosage form, and may be suitably packaged, for example in a box,blister, vial, bottle, sachet, ampoule or in any other suitablesingle-dose or multi-dose holder or container (which may be properlylabeled); optionally with one or more leaflets containing productinformation and/or instructions for use. Generally, such unit dosageswill contain between 1 and 1000 mg, and usually between 5 and 500 mg, ofthe at least one compound of the invention, e.g. about 10, 25, 50, 100,200, 300 or 400 mg per unit dosage.

The compounds can be administered by a variety of routes including theoral, rectal, ocular, transdermal, subcutaneous, intravenous,intramuscular or intranasal routes, depending mainly on the specificpreparation used and the condition to be treated or prevented, and withoral and intravenous administration usually being preferred. The atleast one compound of the invention will generally be administered in an“effective amount”, by which is meant any amount of a compound ofFormula or any subgroup thereof that, upon suitable administration, issufficient to achieve the desired therapeutic or prophylactic effect inthe individual to which it is administered. Usually, depending on thecondition to be prevented or treated and the route of administration,such an effective amount will usually be between 0.01 to 1000 mg perkilogram body weight day of the patient per day, more often between 0.1and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20,50, 100, 150, 200 or 250 mg, per kilogram body weight day of the patientper day, which may be administered as a single daily dose, divided overone or more daily doses, or essentially continuously, e.g. using a dripinfusion. The amount(s) to be administered, the route of administrationand the further treatment regimen may be determined by the treatingclinician, depending on factors such as the age, gender and generalcondition of the patient and the nature and severity of thedisease/symptoms to be treated. Reference is again made to U.S. Pat.Nos. 6,372,778, 6,369,086, 6,369,087 and U.S. Pat. No. 6,372,733 and thefurther prior art mentioned above, as well as to the standard handbooks,such as the latest edition of Remington's Pharmaceutical Sciences.

In accordance with the method of the present invention, saidpharmaceutical composition can be administered separately at differenttimes during the course of therapy or concurrently in divided or singlecombination forms. The present invention is therefore to be understoodas embracing all such regimes of simultaneous or alternating treatmentand the term “administering” is to be interpreted accordingly.

For an oral administration form, the compositions of the presentinvention can be mixed with suitable additives, such as excipients,stabilizers, or inert diluents, and brought by means of the customarymethods into the suitable administration forms, such as tablets, coatedtablets, hard capsules, aqueous, alcoholic, or oily solutions. Examplesof suitable inert carriers are gum arabic, magnesia, magnesiumcarbonate, potassium phosphate, lactose, glucose, or starch, inparticular, corn starch. In this case, the preparation can be carriedout both as dry and as moist granules. Suitable oily excipients orsolvents are vegetable or animal oils, such as sunflower oil or codliver oil. Suitable solvents for aqueous or alcoholic solutions arewater, ethanol, sugar solutions, or mixtures thereof. Polyethyleneglycols and polypropylene glycols are also useful as further auxiliariesfor other administration forms. As immediate release tablets, thesecompositions may contain microcrystalline cellulose, dicalciumphosphate, starch, magnesium stearate and lactose and/or otherexcipients, binders, extenders, disintegrants, diluents and lubricantsknown in the art.

When administered by nasal aerosol or inhalation, these compositions maybe prepared according to techniques well-known in the art ofpharmaceutical formulation and may be prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or othersolubilizing or dispersing agents known in the art. Suitablepharmaceutical formulations for administration in the form of aerosolsor sprays are, for example, solutions, suspensions or emulsions of thecompounds of the invention or their physiologically tolerable salts in apharmaceutically acceptable solvent, such as ethanol or water, or amixture of such solvents. If required, the formulation can alsoadditionally contain other pharmaceutical auxiliaries such assurfactants, emulsifiers and stabilizers as well as a propellant.

For subcutaneous administration, the compound according to theinvention, if desired with the substances customary therefore such assolubilizers, emulsifiers or further auxiliaries are brought intosolution, suspension, or emulsion. The compounds of the invention canalso be lyophilized and the lyophilizates obtained used, for example,for the production of injection or infusion preparations. Suitablesolvents are, for example, water, physiological saline solution oralcohols, e.g. ethanol, propanol, glycerol, in addition also sugarsolutions such as glucose or mannitol solutions, or alternativelymixtures of the various solvents mentioned. The injectable solutions orsuspensions may be formulated according to known art, using suitablenon-toxic, parenterally-acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodiumchloride solution, or suitable dispersing or wetting and suspendingagents, such as sterile, bland, fixed oils, including synthetic mono- ordiglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, theseformulations may be prepared by mixing the compounds according to theinvention with a suitable non-irritating excipient, such as cocoabutter, synthetic glyceride esters or polyethylene glycols, which aresolid at ordinary temperatures, but liquefy and/or dissolve in therectal cavity to release the drug.

In preferred embodiments, the compounds and compositions of theinvention are used orally or parenterally.

The invention will now be illustrated by means of the followingsynthetic and biological examples, which do not limit the scope of theinvention in any way.

EXAMPLES A. Compound Synthesis and Physicochemical Properties

The compounds of this invention can be prepared by any of severalstandard synthetic processes commonly used by those skilled in the artof organic chemistry. The compounds are generally prepared from startingmaterials which are either commercially available or prepared bystandard means obvious to those skilled in the art.

General Schemes:

In general the compounds of formula (I) can be prepared as shown inscheme 1 below wherein a pyrazolo[1,5-a]pyrimidine or aimidazo[2,1-f]pyridazine of formula (II) is converted by reaction with acompound of formula (III) into a compound of formula (IV), which is thenreacted with a (hetero-)aryl of formula (V) to form a compound offormula (VI). The compound of formula (VI) can then be optionallydeprotected if desired before cyclisation to form a compound of formula(VII). The compound of formula (VII) can be optionally converted into acompound of general formula (I).

In the above scheme:

LG₁ and LG₂ each independently represent suitable leaving or functionalgroups;

X₃ and X₄ together with the functional moiety to which they are attachedrepresent an unprotected or a protected functional group which uponreaction (after deprotection) produce together X₁ as defined in formulaI;

E represents a suitable functional group that can be used to form adirect bond between the (hetero-)aryl group and the scaffold.

D represents a functional group such as Y or a protected functionalgroup, which upon further reaction and/or deprotection produces afunctional group such as Y as defined in formula I;

In the above reaction of the compound of formula (II) with the compoundof formula (III) the leaving groups LG₁ and LG₂ are advantageously ahalo group such as a chlorine or a bromine group. The reaction can beaffected by a substitution for example by treating the compound offormula (II) with the compound of formula (III) in an organic solventsuch as acetonitrile with an appropriate base such as for examplediisopropylethylamine at an elevated temperature for example underreflux.

Compounds of formula (III) can be obtained through various selectiveprotection and deprotection steps. The protection reactions can beeffected using for example isoindoline-1,3-dione in a solvent such astoluene at an elevated temperature for example reflux or it can beeffected by using for example benzaldehyde in the presence of a reducingagent for example sodium triacetoxyborohydride in a solvent such as1,2-dichloroethane at room temperature or it can be effected using forexample tert-butyldimethylsilyl chloride and triethylamine in a solventsuch as N,N-dimethylformamide at room temperature. The deprotectionreaction can be effected in a conventional manner using for examplehydrazine in a solvent such as ethanol at an elevated temperature forexample under reflux.

The compound of formula (IV) can optionally be protected with a suitableprotecting group such as a tert-butyloxycarbonylamino group in aconventional manner for example by treatment with tert-butoxycarbonylanhydride in basic conditions using for example triethylamine and4-(dimethylamino)pyridine in a solvent such as tetrahydrofurane at anelevated temperature such as under reflux.

The reaction of the resulting compound (IV) with a (hetero-)arylcompound of formula (V) is advantageously effected through the couplingof a boronic acid E or boronic ester E derivative of the (hetero-)arylcompound under Suzuki conditions using for exampletetrakis(triphenylphosphine)palladium(0),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) andpotassium phosphate tribasic in a solvent mixture such as1,4-dioxane/water at an elevated temperature for example under reflux.

The resulting compound of formula (VI) can optionally be treated toremove any desired protecting groups for example silyl ether groups suchas tert-butyldimethylsilyl groups can be converted to the parent freehydroxy group. Such deprotection can be effected in a conventionalmanner for example using tetrabutylammonium fluoride in tetrahydrofuranat room temperature. The resulting compound of formula (VI) can alsooptionally be treated to remove any desired protecting groups forexample benzyl groups can be removed in a conventional manner forexample using hydrogen gas and palladium on activated charcoal (10%) ina solvent such as methanol at a temperature such as room temperature.The compound of formula (VI) can optionally be treated to remove anydesired protecting groups for example tert-butyloxycarbonylamino groupscan be converted to the parent free amino group. Such deprotection canbe effected in a conventional manner for example by treatment underacidic conditions for example using a 4N acetyl chloride solution in asolvent such as methanol at for example room temperature.

The cyclisation of the compound of formula (VI) can be effected forexample under Mitsunobu conditions using for example diisopropylazodicarboxylate and triphenylphosphine in a solvent mixture such as2-methyl-1,4-dioxane and toluene at an elevated temperature such as 90°C.

The resulting compound of formula (VII) can optionally be treated toremove any desired protecting groups for exampletert-butyloxycarbonylamino groups can be converted to the parent freeamino group. Such deprotection can be effected in a conventional mannerfor example by treatment under acidic conditions for example using a 4Nhydrochloric acid solution in methanol at room temperature.

The compounds of formula (I) can also be prepared as shown in generalscheme 2 below wherein a pyrazolo[1,5-a]pyrimidine or aimidazo[2,1-f]pyridazine of formula (II) is converted by reaction with acompound of formula (VIII) into a compound of formula (IX). The compoundof formula (IX) can be optionally be converted into a compound offormula (IV) which is then reacted with a (hetero-)aryl of formula (V)to form a compound of formula (VI). The compound of formula (VI) canthen be optionally deprotected if desired before cyclisation to form acompound of formula (VII). The compound of formula (VII) can beoptionally converted into a compound of general formula (I).

In the above scheme:

LG₁ and LG₂ each independently represent suitable leaving or functionalgroups;

E represents a suitable functional group that can be used to form adirect bond between the (hetero-)aryl group and the scaffold.

G represents a suitable functional group or protected functional group,which upon further reaction and/or deprotection produces a functionalgroup such as D;

D represents a functional group such as B or a protected functionalgroup, which upon further reaction and/or deprotection produces afunctional group such as B as defined in formula I;

In the above reaction of the compound of formula (II) with the compoundof formula (VIII) the leaving groups LG₁ and LG₂ are advantageously ahalo group such as a chlorine or a bromine group. The reaction can beaffected by a substitution for example by treating the compound offormula (II) with the compound of formula (VIII) in an organic solventsuch as tetrahydrofuran with an appropriate base such as for examplesodium hydride at for example room temperature. Compounds of formula(VIII) can be either commercially acquired or obtained through variousselective protection and deprotection steps.

The compounds of formula (IX) can be deprotected using for exampleacidic conditions such as a 4N hydrochloric acid solution in methanol atroom temperature.

The compounds of formula (IX) can be converted into compounds of formula(IV) by using for example a reductive amination. The reaction can beaffected by treating the compound of formula (IX) with an alhyde in thepresence of a reducing agent such as sodium triacetoxy borohydride and abase such as triethylamine in a solvent such as dichloromethane at forexample room temperature.

The reaction of the compound with formula (IV) with a (hetero-)arylcompound of formula (V) is advantageously effected under Suzukiconditions using for example tetrakis(triphenylphosphine)palladium(0)and potassium phosphate tribasic in a solvent mixture such as1,4-dioxane/water at an elevated temperature for example 80° C.

The resulting compound of formula (VI) can optionally be treated toremove any desired protecting groups for example silyl ether groups suchas tert-butyldimethylsilyl groups can be converted to the parent freehydroxy group. Such deprotection can be effected using for exampleacetic acid in tetrahydrofuran at for example room temperature. Thecompound of formula (VI) can optionally be treated to remove any desiredprotecting groups for example tert-butyloxycarbonylamino groups can beconverted to the parent free amino group. Such deprotection can beeffected in a conventional manner for example by treatment under acidicconditions for example using a 4N acetyl chloride solution in a solventsuch as methanol at for example room temperature.

The free hydroxyl group can be converted into a leaving group such as achloride by reacting the hydroxyl group for example with thionylchloride in the presence of a base such as pyridine in a solvent such asdichloromethane at an elevated temperature for example under reflux.

The cyclisation of the compound of formula (VII) can be advantageouslyeffected under Williamson conditions using a base such as cesiumcarbonate in a solvent such as N,N-dimethylformamide at an elevatedtemperature such as 90° C. Other conditions that can be used for thecyclisation of the compound of formula (VII) can be for example bytreatment with O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU) and N,N-diisopropylethylamine in a solventsuch as N,N-dimethylformamide at for example room temperature.

Conversion into B The resulting compound of formula (VII) can optionallybe treated to form a compound of formula (I).

The above general processes are illustrated by the following specificprocesses which describe the preparation of the compounds of formula(I).

Experimental Part

In obtaining the compounds described in the examples, the followingexperimental protocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature. Where solutions were “dried”, they were generallydried over a drying agent such as sodium sulfate or magnesium sulfate.Where mixtures, solutions and extracts were “concentrated”, they weretypically concentrated on a rotary evaporator under reduced pressure.

For some compounds that were purified by reversed phase high-performanceliquids chromatography (HPLC) the used method is described below(indicated in the compound procedure with HPLC method A. When necessary,these methods can be slightly adjusted by a person skilled in the art toobtain a more optimal result for the separation.

HPLC Method A

The crude product was purified by reverse phase HPLC, using a Gilsonsemi-preparative HPLC system operated by Gilson UNIPOINT software.

The purification was carried out on a Phenomenex Luna column (100 mmlong×21.2 mm i.d.; 5 μm particles) at room temperature, with a constantflow rate of 20.0 mL/min. A gradient elution was performed from 32% (25mM NH4HCO3 aqueous solution)/68% (Acetonitrile-Methanol 1:1) to 4% (25mM NH4HCO3 aqueous solution)/96% (Acetonitrile-Methanol 1:1) in 20minutes. The UV detector was set to 226 nm, which corresponds to thewavelength of maximum absorbance observed for the compound.

Preparation of the Compounds Example 1

Example 1 is prepared following general scheme 1.

Preparation of Intermediate 1

A mixture of 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine (5.00 g, 21.51mmol), 2-(2-aminoethoxyl)ethanol (2.37 ml, 23.66 mmol) andN,N-diisopropylethylamine (4.50 ml, 25.81 mmol) in acetonitrile (65 ml)was refluxed overnight. The reaction mixture was cooled and the solventwas removed under reduced pressure. The residue was dissolved in ethylacetate and washed with water and brine. The organic layer was dried,filtered and the solvent was removed under reduced pressure. The residuewas purified by flash column chromatography over silica gel usingheptane and ethyl acetate as eluents. The product fractions werecollected and the solvent was evaporated.

LCMS method 1: MH⁺=301, RT=0.586 min

Preparation of Intermediate 2

Tert-butyldimethylsilyl chloride (4.86 g, 32.27 mmol) was added to asuspension of intermediate 1 (21.51 mmol) and triethylamine (5.96 ml,43.02 mmol) in N,N-dimethylformamide (65 ml). The mixture was stirred atroom temperature for 1 hour. The reaction mixture was diluted with ethylacetate and washed with water and brine (3×). The organic layer wasdried, filtered and the solvent was removed under reduced pressure. Theproduct was used in the next step without further purification.

LCMS method 1: MH⁺=417, RT=1.783 min

Preparation of Intermediate 3

A mixture of intermediate 2 (21.51 mmol), tert-butoxycarbonyl anhydride(5.16 g, 52.81 mmol), triethylamine (2.61 ml, 25.81 mmol) and4-(dimethylamino)pyridine (53 mg, 0.43 mmol) in tetrahydrofurane (65 ml)was refluxed for 3 hours. The reaction mixture was cooled and thesolvent was removed under reduced pressure. The residue was dissolved inethyl acetate and washed with water and brine. The organic layer wasdried, filtered and the solvent was removed under reduced pressure. Theresidue was purified by flash column chromatography over silica gelusing heptane and ethyl acetate as eluents. The product fractions werecollected and the solvent was evaporated.

Yield: 9.30 g of intermediate 3 (84%, yield over 3 steps)

LCMS method 1: MH⁺=415 (MW-Boc), RT=2.438 min

Preparation of Intermediate 4

To a stirred solution of 2,4-dihydroxybenzoic acid (20.00 g, 129.77mmol) in MeOH (100 ml) was added dropwise at 0° C. a solution ofsulfuric acid (96%) in MeOH (290 ml). The reaction mixture was refluxedovernight. The reaction mixture was cooled and the solvent was removedunder reduced pressure. The residue was dissolved in ethyl acetate andwashed with brine. The organic layer was dried, filtered and the solventwas removed under reduced pressure. The residue was purified by flashcolumn chromatography over silica gel using heptane and ethyl acetate aseluents. The product fractions were collected and the solvent wasevaporated.

LCMS method 1: MH⁺=169, RT=0.660 min

Preparation of Intermediate 5

Trifluoromethanesulfonic anhydride (5.97 ml, 35.32 mmol) was addeddropwise at 0° C. under nitrogen atmosphere to a solution ofintermediate 4 (5.40 g, 32.11 mmol) and triethylamine (8.90 ml, 64.22mmol) in dichloromethane (96 ml). The mixture was allowed to warm up toroom temperature. Water was added and the aqueous phase extracted withdichloromethane. The organic layers were combined, dried, filtered andthe solvent was removed under reduced pressure. The residue was purifiedby flash chromatography over silica gel using heptane and ethyl acetateas eluents. The product fractions were collected and the solvent wasevaporated.

Yield: 3.40 g of intermediate 5 (35%)

LCMS method 1: MH⁺=301, RT=1.458 min

Preparation of Intermediate 6

1,4-Dioxane (27 ml) was degassed by bubbling nitrogen gas through it.Intermediate 5 (2.75 g, 9.16 mmol), bis(pinacolato)diboron (2.33 g, 9.16mmol), tris(dibenzylideneacetone)dipalladium(0) (82 mg, 0.09 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (348 mg, 0.73mmol) were added. The suspension was stirred under nitrogen atmosphereat 110° C. for 30 minutes. The reaction mixture was cooled and was usedas such in the next step.

LCMS method 1: MH⁺=279, RT=1.599 min

Preparation of Intermediate 7

A solution of intermediate 3 (4.25 g, 8.24 mmol) in 1,4-dioxane (8.24ml) and a solution of potassiumphosphate (7.78 g, 36.64 mmol) in water(7.33 ml) were added to crude intermediate 6 (9.16 mmol). The mixturewas stirred at 110° C. for 1 hour. The reaction mixture was cooled,diluted with ethyl acetate and the organic layer was washed with waterand brine. The organic layer was dried, filtered and the solvent wasremoved under reduced pressure. The residue was purified by flash columnchromatography over silica gel using heptane and ethyl acetate aseluents. The product fractions were collected and the solvent wasevaporated.

Yield: 3.46 g of intermediate 7 (64%)

LCMS method 1: MH⁺=487 (MW-Boc), RT=2.544 min

Preparation of Intermediate 8

A mixture of intermediate 7 (3.46 g, 5.90 mmol) and tetrabutylammoniumfluoride (2.31 g, 8.85 mmol) in tetrahydrofuran (18 ml) was stirred atroom temperature for 1 hour. The solvent was removed under reducedpressure, the residue was dissolved in ethyl acetate and washed withwater (3×) and brine. The organic layer was dried, filtered and thesolvent was removed under reduced pressure. The residue was purified byflash chromatography over silica gel using dichloromethane and methanolas eluents. The product fractions were collected and the solvent wasevaporated.

LCMS method 1: MH⁺=473, RT=1.425 min

Preparation of Intermediate 9

A solution of intermediate 8 (2.45 g, 5.19 mmol) in2-methyltetrahydrofuran (20 ml/mmol) and a solution of diisopropylazodicarboxylate (3.09 g, 15.57 mmol) in toluene (20 ml/mmol) were addedsimultaneously to a solution of triphenylphosphine (4.08 g, 15.57 mmol)in toluene (75 ml/mmol). The mixture was stirred at 90° C. for 3 hours.The reaction mixture was cooled and the solvent was removed underreduced pressure. The residue was triturated in ethyl acetate andfiltered to give the desired product.

Yield: 1.75 g of intermediate 9 (74%)

LCMS method 1: MH⁺=455, RT=1.505 min

Preparation of Example 1

Intermediate 9 (1.75 g, 3.85 mmol) and lithium hydroxide monohydrate(12.00 g, 11.55 mmol) were suspended in tetrahydrofuran/methanol (1:1,12 ml). The mixture was stirred overnight at 50° C. The reaction mixturewas cooled and 1N hydrochloric acid in water was added to obtain pH 3.The solvent was removed under reduced pressure and purified by flashchromatography on silica gel using dichloromethane and methanol aseluents. The product fractions were collected and the solvent wasevaporated. The obtained solid was triturated in methanol to yield thedesired product.

Yield: 705 mg of example 1 (54%)

LCMS method 1: MH⁺=341, RT=0.696 min

Example 2

Example 2 is prepared following general scheme 1.

Preparation of Intermediate 10

A mixture of 1,4-dioxane and water (3:1, 40 ml) was degassed by bubblingnitrogen gas through the mixture. Intermediate 3 (1.85 g, 3.59 mmol),(3-aminophenyl)boronic acid (0.72 g, 4.67 mmol),tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.04 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (67 mg,0.14 mmol) and potassium phosphate tribasic (5 eq.) were added and themixture was stirred under nitrogen gas at 80° C. for 2 hours. Thereaction mixture was cooled, diluted with ethyl acetate and the organiclayer was washed with brine. The organic layer was dried, filtered andthe solvent was removed under reduced pressure. The residue was purifiedby flash column chromatography over silica gel using heptane and ethylacetate as eluents. The product fractions were collected and the solventwas evaporated.

Yield: 1.64 g of intermediate 10 (87%)

LCMS method 1: MH⁺=528, RT=2.129 min

Preparation of Intermediate 11

2-Nitrobenzenesulfonyl chloride (0.83 g, 3.73) mmol was addedportionwise at 0° C. and under nitrogen atmosphere to a solution ofintermediate 10 (1.64 g, 3.11 mmol), triethylamine (0.56 ml, 4.04 mmol)and 4-dimethylaminopyridine (20 mg, 0.16 mmol) in dichloromethane (20ml). The reaction mixture was allowed to warm up to room temperature andstirred overnight. The crude reaction mixture was diluted with ethylacetate and washed with a saturated aqueous sodium bicarbonate solution,water and brine. The organic layer was dried, filtered and the solventwas removed under reduced pressure. The residue was purified by flashcolumn chromatography over silica gel using heptane and ethyl acetate aseluents. The product fractions were collected and the solvent wasevaporated.

Yield: 1.32 g of intermediate 11 (55%)

LCMS method 1: MH⁺=613 (MW-Boc), RT=2.328 min

Preparation of Intermediate 12

A mixture of intermediate 11 (1.24 g, 1.73 mmol) and tetrabutylammoniumfluoride (0.68 g, 2.59 mmol) in tetrahydrofuran (5 ml) was stirred atroom temperature for 1 hour. The solvent was removed under reducedpressure, the residue was dissolved in ethyl acetate and washed withwater (3×) and brine. The organic layer was dried, filtered and thesolvent was removed under reduced pressure. The residue was used in thenext step without further purification.

LCMS method 1: MH⁺=599, RT=1.322 min

Preparation of Intermediate 13

A solution of intermediate 12 (1.13 g, 1.89 mmol) in2-methyltetrahydrofuran (20 ml/mmol) and a solution of diisopropylazodicarboxylate (1.12 g, 5.67 mmol) in toluene (20 ml/mmol) were addedsimultaneously to a solution of triphenylphosphine (1.49 g, 5.67 mmol)in toluene (75 ml/mmol). The mixture was stirred at 90° C. for 3 hours.The reaction mixture was cooled and the solvent was removed underreduced pressure. The residue was purified by flash columnchromatography over silica gel using heptane and ethyl acetate aseluents. The product fractions were collected and the solvent wasevaporated.

LCMS method 1: MH⁺=581, RT=1.700 min

Preparation of Intermediate 14

Intermediate 13 (1.89 mmol) and cesium carbonate (1.23 g, 3.78 mmol)were suspended in N,N-dimethylformamide (6 ml). Thiophenol (230 μl, 2.27mmol) was added and the mixture was stirred at room temperature for 2hours. The reaction mixture was diluted with ethyl acetate and washedwith brine. The organic layer was dried, filtered and the solvent wasremoved under reduced pressure. The residue was purified by flash columnchromatography over silica gel using dichloromethane and methanol aseluents. The product fractions were collected and the solvent wasevaporated.

Yield: 0.50 g of intermediate 14 (67%)

LCMS method 1: MH⁺=396, RT=1.346 min

Preparation of Example 2

Phosphorus trichloride (66 mg, 0.76 mmol) was added to a suspension ofintermediate 14 (0.300 g, 0.76 mmol) and 1-methylpiperidine-4-carboxylicacid hydrochloride (0.15 g, 0.76 mmol) in acetonitrile (2.3 ml) in asealed tube. The mixture was heated by microwave at 150° C. for 10 min.The reaction mixture was poured into a saturated aqueous sodiumbicarbonate solution and extracted with dichloromethane (3×). Theorganic layer was dried, filtered and the solvent was removed underreduced pressure. The residue was purified by flash columnchromatography over silica gel using dichloromethane and methanol aseluents. The product fractions were collected and the solvent wasevaporated.

Yield: 210 g of example 2 (66%)

LCMS method 1: MH⁺=421, RT=0.531 min

Example 3

Example 3 is prepared following general scheme 1.

Preparation of Intermediate 15

A mixture of 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine (1.00 g, 4.30mmol), tert-butyl N-(3-aminopropyl)carbamate (0.82 g, 4.73 mmol) andN,N-diisopropylethylamine (0.91 ml, 5.16 mmol) in acetonitrile (13 ml)was refluxed overnight. The reaction mixture was cooled and the solventwas removed under reduced pressure. The residue was dissolved in ethylacetate and washed with water and brine. The organic layer was dried,filtered and the solvent was removed under reduced pressure. The residuewas purified by flash column chromatography over silica gel usingheptane and ethyl acetate as eluents. The product fractions werecollected and the solvent was evaporated.

Yield: 1.58 g of intermediate 15 (99%)

LCMS method 1: MH⁺=372, RT=1.104 min

Preparation of Intermediate 16

A mixture of intermediate 15 (1.58 g, 4.27 mmol), tert-butoxycarbonylanhydride (0.98 g, 4.48 mmol), triethylamine (0.68 ml, 4.91 mmol) and4-(dimethylamino)pyridine (26 mg, 0.21 mmol) in tetrahydrofuran (13 ml)was refluxed for 2 hours. The reaction mixture was cooled and thesolvent was removed under reduced pressure. The residue was dissolved inethyl acetate and washed with water and brine. The organic layer wasdried, filtered and the solvent was removed under reduced pressure. Theresidue was used in the next step without further purification.

LCMS method 1: MH⁺=370 (MW-Boc), RT=1.712 min

Preparation of Intermediate 17

A mixture of 1,4-dioxane and water (3:1, 7.6 ml) was degassed bybubbling nitrogen gas through the mixture. Intermediate 16 (1.18 g, 2.52mmol), (3-aminophenyl)boronic acid (0.47 g, 3.02 mmol),tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (48 mg,0.10 mmol) and potassium phosphate tribasic (5 eq.) were added and themixture was stirred under nitrogen gas at 80° C. overnight. The reactionmixture was cooled, diluted with ethyl acetate and the organic layer waswashed with brine. The organic layer was dried, filtered and the solventwas removed under reduced pressure. The residue was purified by flashcolumn chromatography over silica gel using heptane and ethyl acetate aseluents. The product fractions were collected and the solvent wasevaporated.

Yield: 1.04 g of intermediate 17 (86% over 2 steps)

LCMS method 1: MH⁺=483, RT=1.379 min

Preparation of Intermediate 18

Intermediate 17 (1.04 g, 2.16 mmol) was dissolved in 4N hydrochloricacid in methanol (20 ml). The mixture was stirred at room temperatureovernight. The reaction mixture was diluted with ethyl acetate and theorganic layer was washed with a saturated aqueous sodium bicarbonatesolution. The organic layer was dried, filtered and the solvent wasremoved under reduced pressure. The residue was purified by flash columnchromatography over silica gel using dichloromethane and methanol withammonia as eluents. The product fractions were collected and the solventwas evaporated.

Yield: 0.40 g of intermediate 17 (66%)

LCMS method 1: MH⁺=283, RT=0.194 min

Preparation of Example 3

Triphosgene (10 mg, 0.05 mmol) was added to a solution of intermediate17 (50 mg, 0.18 mmol) in dichloromethane (0.54 ml). The reaction mixturewas stirred at room temperature for 3 hours. The reaction mixture wasdiluted with dichloromethane and the organic layer was washed withwater. The organic layer was dried, filtered and the solvent was removedunder reduced pressure. The residue was purified by reversed phasecolumn chromatography (HPLC method A).

Yield: 7 mg of Example 3 (13%)

LCMS method 2: MH⁺=309, RT=2.181 min

Example 4

Example 4 is prepared following general scheme 1.

Preparation of Intermediate 18

A mixture of 2-(2-aminoethylamino)ethanol (14.56 g, 139.80 mmol) andisoindoline-1,3-dione (20.16 g, 137.00 mmol) in toluene (420 ml) wasrefluxed for 3 hours. The solvent was removed under reduced pressure andthe residue was used in the next step without further purification.

LCMS method 1: MH⁺=235, RT=0.181 min

Preparation of Intermediate 19

Tert-butyldimethylsilyl chloride (31.0 g, 205.5 mmol) was added to asuspension of intermediate 18 (32.0 g, 137.0 mmol) and triethylamine(38.0 ml, 274.0 mmol) in N,N-dimethylformamide (411 ml). The mixture wasstirred overnight at room temperature. The reaction mixture was dilutedwith ethyl acetate and washed with water and brine (3×). The organiclayer was dried, filtered and the solvent was removed under reducedpressure. The residue was purified by flash column chromatography usingheptane and ethyl acetate as eluents. The product fractions werecollected and the solvent was evaporated.

Yield: 16.6 g of intermediate 19 (35%)

LCMS method 1: MH⁺=349, RT=0.728 min

Preparation of Intermediate 20

Tert-butoxycarbonyl anhydride (4.3 g, 19.6 mmol) was added to a mixtureof intermediate 19 (6.5 g, 18.6 mmol) and triethylamine (3.1 ml, 22.4mmol) in tetrahydrofuran (56 ml). The reaction mixture was stirred for 1hour and the solvent was removed under reduced pressure. The residue wasdissolved in ethyl acetate and washed with water and brine (3×). Theorganic layer was dried, filtered and the solvent was removed underreduced pressure. Intermediate 3 was used in the next step withoutfurther purification.

Yield: 6.0 g of intermediate 20 (72%)

LCMS method 1: MH⁺=349 (MW-Boc), RT=2.185 min

Preparation of Intermediate 21

A mixture of intermediate 20 (6.0 g, 13.4 mmol) and hydrazine (1.2 ml,40.1 mmol) was stirred overnight at 60° C. The reaction mixture wascooled, filtered and the solvent was removed under reduced pressure. Theresidue was dissolved in ethyl acetate and washed with 1N sodiumhydroxide and water. The organic layer was dried, filtered and thesolvent was removed under reduced pressure. Intermediate 4 was used inthe next step without further purification.

Yield: 3.8 g of intermediate 21 (89%)

LCMS method 1: MH⁺=319, RT=0.948 min

Preparation of Intermediate 22

A mixture of 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine (2.5 g, 10.7mmol), intermediate 21 (3.8 g, 11.8 mmol) and N,N-diisopropylethylamine(2.2 ml, 12.9 mmol) in acetonitrile (32 ml) was refluxed overnight. Thereaction mixture was cooled and the solvent was removed under reducedpressure. The residue was dissolved in ethyl acetate and washed withwater and brine. The organic layer was dried, filtered and the solventwas removed under reduced pressure. The residue was purified by flashcolumn chromatography over silica gel using heptane and ethyl acetate aseluents. The product fractions were collected and the solvent wasevaporated.

Yield: 4.7 g of intermediate 22 (84%)

LCMS method 1: MH⁺=516, RT=2.154 min

Preparation of Intermediate 23

A mixture of intermediate 22 (4.7 g, 9.1 mmol), tert-butoxycarbonylanhydride (2.1 g, 9.5 mmol), triethylamine (1.4 ml, 10.0 mmol) and4-(dimethylamino)pyridine (0.05 g, 0.45 mmol) in tetrahydrofuran (27 ml)was refluxed overnight. The reaction mixture was cooled and the solventwas removed under reduced pressure. The residue was dissolved in ethylacetate and washed with water and brine. The organic layer was dried,filtered and the solvent was removed under reduced pressure. The residuewas purified by flash column chromatography over silica gel usingheptane and ethyl acetate as eluents. The product fractions werecollected and the solvent was evaporated.

Yield: 5.2 g of intermediate 23 (92%)

LCMS method 1: MH⁺=516 (MW-Boc), RT=2.615 min

Preparation of Intermediate 24

A mixture of 1,4-dioxane and water (3:1, 62 ml) was degassed by bubblingnitrogen gas through the mixture. Intermediate 23 (3.83 g, 6.23 mmol),methyl 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(2.25 g, 8.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (55 mg,0.06 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl(Xphos) (119 mg, 0.25 mmol) and potassium phosphate tribasic (5.28 g, 4eq.) were added and the mixture was stirred under nitrogen gas at 80° C.for 2 hours. The reaction mixture was cooled, diluted with ethyl acetateand the organic layer was washed with brine. The organic layer wasdried, filtered and the solvent was removed under reduced pressure. Theresidue was purified by flash column chromatography over silica gelusing heptane and ethyl acetate as eluents. The product fractions werecollected and the solvent was evaporated.

Yield: 1.88 g of intermediate 24 (44%)

LCMS method 1: MH⁺=572 (MW-Me-Boc), RT=2.303 min

Preparation of Intermediate 25

A mixture of intermediate 24 (1.88 g, 2.74 mmol) and tetrabutylammoniumfluoride (1.07 g, 4.11 mmol) in tetrahydrofuran (8 ml) was stirred atroom temperature for 1 hour. The solvent was removed under reducedpressure. The residue was purified by flash column chromatography oversilica gel using heptane and ethyl acetate as eluents. The productfractions were collected and the solvent was evaporated.

Yield: 1.51 g of intermediate 25 (96%)

LCMS method 1: MH⁺=472 (MW-Boc, RT=1.691 min

Preparation of Intermediate 26

A solution of intermediate 25 (1.51 g, 2.64 mmol) in2-methyltetrahydrofuran (20 ml/mmol) and a solution of diisopropylazodicarboxylate (1.57 g, 7.92 mmol) in toluene (20 ml/mmol) were addedsimultaneously to a solution of triphenylphosphine (2.08 g, 7.92 mmol)in toluene (75 ml/mmol). The mixture was stirred at 90° C. for 3 hours.The reaction mixture was cooled and the solvent was removed underreduced pressure. The residue was purified by flash columnchromatography over silica gel using heptane and ethyl acetate aseluents. The product fractions were collected and the solvent wasevaporated. The residue was triturated in methanol and filtered to givethe desired product.

Yield: 0.60 g of intermediate 26 (41%)

LCMS method 1: MH⁺=454 (MW-Boc), RT=2.031 min

Preparation of Intermediate 27

Intermediate 26 (0.60 g, 1.08 mmol) and lithium hydroxide monohydrate(0.23 g, 3.24 mmol) were suspended in tetrahydrofuran/methanol (1:1, 3ml). The mixture was stirred overnight at 50° C. The reaction mixturewas cooled and the solvent was removed under reduced pressure andpurified by flash chromatography on silica gel using dichloromethane andmethanol as eluents. The product fractions were collected and thesolvent was evaporated.

Preparation of Intermediate 28

Intermediate 27 (1.08 mmol), ammonium chloride (0.13 g, 2.38 mmol) andN,N-diisopropylethylamine (0.5 ml, 2.81 mmol) were dissolved inN,N-dimethylformamide (3 ml).O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) (0.98 g, 2.59 mmol) was added and the reaction mixture wasstirred at room temperature for 1 hour. The mixture was poured intoethyl and washed with a saturated aqueous sodium bicarbonate solution,water and brine. The organic layer was dried, filtered and the solventwas removed under reduced pressure. The residue was triturated in hotmethanol, cooled and filtered to give the desired product.

Yield: 392 mg of intermediate 28 (83% over 2 steps)

LCMS method 1: MH⁺=439, RT=1.003 min

Preparation of Example 4

Intermediate 28 (0.39 g, 0.89 mmol) was dissolved in 4N hydrochloricacid in methanol (3 ml). The mixture was stirred at room temperature for2 hours. The solvent was removed under reduced pressure. The resultingsolid was triturated in methanol, filtered and washed with methanol toyield the desired product.

Yield: 325 mg of example 4 (97%)

LCMS method 2: MH⁺=339, RT=1.254 min

Example 5

Example 5 is prepared following general scheme 1.

Example 5 is prepared according to the same methods as for the synthesisof Example 4 using (3-hydroxyphenyl)boronic acid for the Suzukicoupling.

Preparation of Example 5

7-Oxa-10,13,17,18,21-pentaazatetracyclo[12.5.2.1^{2,6}.0^{17,20}]docosa-(20),2,4,6(22),14(21),-15,18-heptaene(200 mg, 0.60 mmol) and triethylamine (0.291 ml, 2.10 mmol) weredissolved in a mixture of 1,2-dichloroethane and methanol (1:1, 5 ml).2-Morpholinoacetaldehyde (0.12 g, 0.72 mmol) was added and the mixturewas stirred at room temperature for 30 minutes. Sodiumtriacetoxyborohydride (254 mg, 1.20 mmol) was added and the mixture wasstirred at room temperature until the reaction was completed (TLC). Thereaction mixture was poured into ethyl acetate and the organic layer waswashed with a saturated aqueous sodium bicarbonate solution and brine.The organic layer was dried, filtered and the solvent was removed underreduced pressure. The residue was purified by flash columnchromatography over silica gel using dichloromethane and methanol aseluents. The product fractions were collected and the solvent wasevaporated.

Yield: 163 mg of example 5 (66%)

LCMS method 1: MH⁺=409, RT=0.606 min

Example 6

Example 6 is prepared following general scheme 1.

Example 6 is prepared according to the same methods used for thesynthesis of Example 5.

Preparation of Example 6

7-Oxa-10,13,17,18,21-pentaazatetracyclo[12.5.2.1^{2,6}.0^{17,20}]docosa-(20),2,4,6(22),14(21),-15,18-heptaene(200 mg, 0.60 mmol) and triethylamine (0.208 ml, 1.50 mmol) weredissolved in a mixture of 1,2-dichloroethane and methanol (1:1, 5 ml).Acetone (0.05 ml, 0.72 mmol) was added and the mixture was stirred atroom temperature for 30 minutes. Sodium triacetoxyborohydride (254 mg,1.20 mmol) was added and the mixture was stirred at room temperatureuntil the reaction was completed (TLC). The reaction mixture was pouredinto ethyl acetate and the organic layer was washed with a saturatedaqueous sodium bicarbonate solution and brine. The organic layer wasdried, filtered and the solvent was removed under reduced pressure. Theresidue was purified by flash column chromatography over silica gelusing dichloromethane and methanol as eluents. The product fractionswere collected and the solvent was evaporated.

Yield: 148 mg of example 6 (73%)

LCMS method 1: MH⁺=338, RT=0.555 min

Example 7

Example 7 is prepared following general scheme 1.

Preparation of Intermediate 29

To a solution of tert-butyl N-[2-(benzenesulfonamido)ethyl]carbamate(21.70 g, 62.83 mmol) in N,N-dimethylformamide (189 ml) were added2-bromoethyl acetate (11.54 g, 69.11 mmol) and cesium carbonate (26.60g, 75.39 mmol). The mixture was stirred overnight at 50° C. Water wasadded and the product was extracted with ethyl acetate. The organiclayer was dried, filtered and the solvent was removed under reducedpressure. The product was used without further purification in the nextstep.

LCMS method 1: MH⁺=332 (MW-Boc), RT=1.151 min

Preparation of Intermediate 30

Sodium hydroxide (2.513 g, 62.83 mmol) was added to a solution ofintermediate 29 (27.11 g, 62.83 mmol) in methanol/water (3:1, 188 ml).The mixture was stirred at room temperature for 90 minutes. The solventwas removed under reduced pressure, water was added and the product wasextracted with ethyl acetate. The organic layer was dried, filtered andthe solvent was removed under reduced pressure. The product was usedwithout further purification in the next step.

LCMS method 1: MH⁺=290 (MW-Boc), RT=0.956 min

Preparation of Intermediate 31

Intermediate 30 (62.83 mmol) was stirred in acetyl chloride (188 ml) atroom temperature for 2 hours. The solvent was removed under reducedpressure. Toluene was added, stirred and removed under reduced pressure.The product was used without further purification in the next step.

LCMS method 1: MH⁺=290, RT=0.219 min

Preparation of Intermediate 32

A mixture of 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine (10.0 g, 43.02mmol), intermediate 31 (18.22 g, 55.92 mmol) andN,N-diisopropylethylamine (22.48 ml, 129.05 mmol) in acetonitrile (129ml) was refluxed overnight. The reaction mixture was cooled and thesolvent was removed under reduced pressure. The residue was dissolved inethyl acetate and washed with water and brine. The organic layer wasdried, filtered and the solvent was removed under reduced pressure. Theresidue was purified by flash column chromatography over silica gelusing dichloromethane and methanol as eluents. The product fractionswere collected and the solvent was evaporated.

Yield: 16.74 g of intermediate 32 (80%)

LCMS method 1: MH⁺=487, RT=0.942 min

Preparation of Intermediate 33

A solution of intermediate 32 (12.66 g, 26.09 mmol) in drytetrahydrofuran (78 ml) was degassed by bubbling nitrogen gas throughthe solution. Isoindoline-1,3-dione (5.76 g, 39.13 mmol) andtriphenylphosphine (10.26 g, 39.13 mmol) were added and the mixture wascooled to 5° C. Diisopropyl azodicarboxylate (7.76 g, 39.13 mmol) wasadded and the mixture was stirred at room temperature for 2 hours. Thesolvent was removed under reduced pressure and water was added. Thewater layer was extracted with ethyl acetate. The organic layer wasdried, filtered and the solvent was removed under reduced pressure. Theproduct was used without further purification in the next step.

LCMS method 1: MH⁺=616, RT=1.225 min

Preparation of Intermediate 34

A mixture of intermediate 33 (12.26 g, 19.96 mmol) and hydrazine (1.86ml, 29.94 mmol) in ethanol (60 ml) was stirred under reflux overnight.The reaction mixture was cooled, filtered and the solvent was removedunder reduced pressure. The residue was dissolved in ethyl acetate andwashed with 1N sodium hydroxide and water. The organic layer was dried,filtered and the solvent was removed under reduced pressure. The productwas used without further purification in the next step.

LCMS method 1: MH⁺=486, RT=0.503 min

Preparation of Intermediate 35

To a solution of intermediate 34 (19.97 mmol) in tetrahydrofuran (60 ml)were added tert-butoxycarbonyl anhydride (10.89 g, 49.91 mmol) and4-(dimethylamino)pyridine (244 mg, 2.00 mmol). The mixture was stirredat room temperature overnight. The solvent was removed under reducedpressure. The residue was purified by flash column chromatography oversilica gel using heptane and ethyl acetate as eluents. The productfractions were collected and the solvent was evaporated.

LCMS method 1: MH⁺=586 (MW-Boc), RT=1.769 min

Preparation of Intermediate 36

A mixture of 1,4-dioxane and water (3:1, 85 ml) was degassed by bubblingnitrogen gas through the mixture. Intermediate 35 (5.78 g, 8.44 mmol),3-boronobenzoic acid (2.10 g, 12.66 mmol),tetrakis(triphenylphosphine)palladium(0) (97 mg, 0.084 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (243 mg,0.51 mmol) and potassium phosphate tribasic (8.96 g, 5 eq.) were addedand the mixture was stirred under nitrogen gas at 80° C. for 5 hours.The reaction mixture was cooled, diluted with ethyl acetate and theorganic layer was washed with water. The organic layer was dried,filtered and the solvent was removed under reduced pressure. The residuewas purified by flash column chromatography over silica gel usingheptane and ethyl acetate and then dichloromethane and methanol aseluents. The product fractions were collected and the solvent wasevaporated.

Yield: 4.75 g of intermediate 36 (78%)

LCMS method 1: MH⁺=626 (MW-Boc), RT=1.586 min

Preparation of Intermediate 37

Intermediate 36 (4.75 g, 6.54 mmol) was dissolved in 4N hydrochloricacid solution in dioxane/water (1:1, 20 ml). The mixture was stirred atroom temperature for 2 hours. The solvent was removed under reducedpressure and toluene was added. The mixture was stirred and the solventwas removed under reduced pressure. The product was used without furtherpurification in the next step.

LCMS method 1: MH⁺=526, RT=0.606 min

Preparation of Intermediate 38

A mixture of intermediate 37 (2.00 g, 3.56 mmol) and 4N acetylchloridein methanol (11 ml) was heated at 60° C. for 54 hours. The solvent wasremoved under reduced pressure and the product was without any furtherpurification used in the next step.

Preparation of Intermediate 39

2-(tert-Butyl(dimethyl)silyl)oxyacetaldehyde (0.854 ml, 4.40 mmol) wasadded to a suspension of intermediate 38 (1.95 g, 3.385 mmol) anddiisopropyl ethylamine (1.768 ml, 10.15 mmol) in methanol (10 ml). Themixture was stirred at room temperature for 1 hour and sodiumborohydride (0.192 g, 5.08 mmol) was added in small portions. Themixture was stirred at room temperature for 1 hour. The solvent wasremoved under reduced pressure, water was added and the product wasextracted with ethyl acetate. The organic layer was dried, filtered andthe solvent was removed under reduced pressure. The product was purifiedby flash chromatography over silica gel using mixtures ofdichloromethane and methanol as eluents. The product fractions werecollected and the solvent was evaporated.

Yield: 748 mg of intermediate 39 (32%)

LCMS method 1: MH⁺=698, RT=1.221 min

Preparation of Intermediate 40

Intermediate 39 (0.748 g, 1.072 mmol) and cesium carbonate (0.755 g,2.14 mmol) were suspended in N,N-dimethylformamide (3 ml). Thiophenol(132 μl, 2.14 mmol) was added and the mixture was stirred at roomtemperature for 3 hours. The solvent was removed under reduced pressure.The residue was purified by flash column chromatography over silica gelusing dichloromethane and methanol as eluents. The product fractionswere collected and the solvent was evaporated.

Yield: 0.496 g of intermediate 40 (90%)

LCMS method 1: MH⁺=513, RT=0.831 min

Preparation of Intermediate 41

Intermediate 40 (0.448 g, 0.874 mmol) and lithium hydroxide monohydrate(37 mg, 0.87 mmol) were suspended in tetrahydrofuran/methanol (1:1, 3.5ml). The mixture was stirred overnight at room temperature. 1N HClsolution was added until pH 7 and the solvent was evaporated twice withtoluene. The TBDMS group was partially removed. The product was usedwithout further purification in the next step.

LCMS method 1: MH⁺=499, RT=0.714 min

Preparation of Example 7

A solution of intermediate 41 (0.434 g, 0.870 mmol) inN,N-dimethylformamide (26 ml) was added dropwise over a period of 2hours to a solution of N,N-diisopropylethylamine (0.90 ml, 5.22 mmol)and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU) (0.99 g, 2.61 mmol) in N,N-dimethylformamide(61 ml). The solvent was removed under reduced pressure and the residuewas purified by reversed phase column chromatography (HPLC method A).The product fractions were collected and the solvent was evaporated.

Yield: 65 mg of example 7 (20%)

LCMS method 2: MH⁺=367, RT=1.223 min

Example 8

Example 8 is prepared following general scheme 1.

Example 8 is prepared according to the synthetic methods used for thepreparation of Example 7.

Preparation of Intermediate 42

8,11,14,18,19,22-Hexaazatetracyclo[13.5.2.1^{2,6}.0^{18,21}]tricosa-1(21),2,4,6(23),15(22),16,19-heptaen-7-one(330 mg, 1.02 mmol), triethylamine (0.357 ml, 2.05 mmol) and2-(tert-butyl(dimethyl)silyl)oxyacetaldehyde (0.258 ml, 1.23 mmol) weredissolved in a mixture of 1,2-dichloroethane and methanol (10:1, 20 ml)and the mixture was stirred at room temperature for 3 hours. Sodiumtriacetoxyborohydride (2.048 mmol) was added in small portions and themixture was stirred at room temperature for 2 hours. The reactionmixture was poured into ethyl acetate and the organic layer was washedwith a saturated aqueous sodium bicarbonate solution and brine. Theorganic layer was dried, filtered and the solvent was removed underreduced pressure. The product was used without further purification inthe next step.

LCMS method 1: MH⁺=481, RT=0.954 min

Preparation of Example 8

Intermediate 42 (0.39 g, 0.81 mmol) in a mixture of aceticacid/water/tetrahydrofuran (3:1:1, 2.43 ml) was stirred at 60° C. for 4hours. The solvent was removed under reduced pressure anddichloromethane was added. A precipitate was formed which was filtered,washed with methanol and dried under vacuum. The solvent of the motherliquor was removed under reduced pressure. The residue was purified byflash column chromatography over silica gel using dichloromethane andmethanol as eluents. The product fractions were collected and thesolvent was evaporated. The residue was added to the solid obtainedafter the addition of dichloromethane.

Yield: 242 mg of example 8 (81%)

LCMS method 2: MH⁺=367, RT=1.256 min

Example 9

Example 9 is prepared following general scheme 1.

Example 9 is prepared according to the synthetic methods used for thepreparation of Example 8.

Preparation of Example 9

Palladium/C (10% wet, 0.24 mmol) was added to a solution of8,11,14,18,19,22-Hexaazatetracyclo[13.5.2.1^{2,6}.0^{18,21}]tricosa-1(21),2,4,6(23),15(22),16,19-heptaen-7-one(77 mg, 0.239 mmol) in N,N-dimethylformamide (0.72 ml). The mixture wasstirred under atmospheric pressure of hydrogen gas at room temperaturefor 48 hours. Methanol (1 ml) and acetic acid (1 ml) were added and themixture was stirred under atmospheric pressure of hydrogen gas at roomtemperature for 24 hours. Methanol (1 ml) and acetic acid (1 ml) andpalladium/C (10% wet, 0.24 mmol) were added and the mixture was againstirred under atmospheric pressure of hydrogen gas at room temperaturefor 48 hours. The reaction mixture was filtered over celite and washedwith dichloromethane and methanol. The solvent was removed under reducedpressure and the product was purified by flash chromatography oversilica gel using dichloromethane and methanol as eluents. The productfractions were collected and the solvent was evaporated.

Yield: 15 mg of example 9 (19%)

LCMS method 2: MH⁺=337, RT=1.290 min

Example 10

Example 10 is prepared following general scheme 1.

Preparation of Intermediate 43

A mixture of7-oxa-10,13,17,18,21-pentaazatetracyclo[12.5.2.1^{2,6}.0^{17,20}]docosa-1(20),2,4,6(22),14(21),15,18-heptaene(0.42 g, 1.27 mmol), tert-butoxycarbonyl anhydride (0.33 g, 1.52 mmol)and triethylamine (0.528 ml, 3.81 mmol) in tetrahydrofurane (4 ml) wasstirred at room temperature overnight. The solvent was removed underreduced pressure. The residue was recrystallized from acetonitrile andthe product was used without further purification in the next step.

LCMS method 1: MH⁺=396, RT=1.472 min

Preparation of Intermediate 44

Triphosgene (0.53 g, 1.78 mmol) was added to a solution of intermediate43 (0.35 mg, 0.89 mmol) in 1,2-dichloroethane (1.2 ml) at 0° C. undernitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 30 minutes. 3-Pyrrolidin-1-ylpropan-1-amine (0.169 ml,1.34 mmol) was added and the mixture was stirred at 50° C. for 30minutes. The reaction mixture was cooled and the solvent was removedunder reduced pressure. The residue was purified by flash columnchromatography over silica gel using heptane and ethyl acetate aseluents. The product fractions were collected and the solvent wasevaporated.

Yield: 0.400 g of intermediate 44 (82%)

LCMS method 2: MH⁺=550, RT=2.550 min

Preparation of Example 10

Intermediate 44 (0.40 g, 0.73 mmol) was dissolved in 4N hydrochloricacid solution in methanol (2 ml). The mixture was stirred at roomtemperature for 3 hours. The formed solid was filtered and dried underhigh vacuum.

Yield: 102 mg of example 10 (31%)

LCMS method 2: MH⁺=451, RT=1.180 min

Example 11

Example 11 is prepared following general scheme 1.

Preparation of Intermediate 45

Triphosgene (0.33 g, 1.12 mmol) was added to a solution of intermediate43 (0.22 mg, 0.56 mmol) in 1,2-dichloroethane (2.6 ml) at 0° C. undernitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 30 minutes. N′,N′-Dimethylethane-1,2-diamine (0.093 ml,0.84 mmol) was added and the mixture was stirred at 50° C. for 30minutes. The reaction mixture was cooled and the solvent was removedunder reduced pressure. The residue was purified by flash columnchromatography over silica gel using heptane and ethyl acetate aseluents. The product fractions were collected and the solvent wasevaporated.

Yield: 0.260 g of intermediate 45 (91%)

Preparation of Example 11

Intermediate 44 (0.26 g, 0.51 mmol) was dissolved in 4N hydrochloricacid solution in methanol (1.5 ml). The mixture was stirred at roomtemperature for 3 hours. The formed solid was filtered and dried underhigh vacuum.

Yield: 189 mg of example 11 (77%)

LCMS method 2: MH⁺=410, RT=1.131 min

Example 12

Example 12 is prepared following general scheme 1.

Preparation of Example 12

Isobutyl carbonochloridate (0.20 g, 1.54 mmol) was added to a solutionof Example 1 (0.435 g, 1.28 mmol) and triethylamine (0.266 ml, 1.92mmol) in tetrahydrofuran (4 ml). The mixture was stirred at roomtemperature for 30 minutes. Sodium borohydride (0.145 g, 3.84 mmol) wasadded at the mixture was refluxed for 30 minutes. Methanol (2 ml/mmol)was added and the mixture was refluxed for 1 hour. The reaction mixturewas cooled and a saturated aqueous ammonium chloride solution was added.The product was extracted with ethyl acetate. The organic layer wasdried, filtered and the solvent was removed under reduced pressure. Theresulting solid was triturated with methanol to yield the desiredproduct.

Yield: 62 mg of example 12 (15%)

LCMS method 2: MH⁺=327, RT=2.223 min

Example 13

Example 13 is prepared following general scheme 2.

Preparation of Intermediate 46

3-pyrrolidin-1-ylpropan-1-amine (3.00 g, 23.40 mmol) and2-(tert-butyl(dimethyl)silyl)oxyacetaldehyde (4.88 ml, 25.74 mmol) weredissolved in methanol (70 ml) and the mixture was stirred at roomtemperature for 30 minutes. Sodium borohydride (0.974 g, 25.74 mmol) wasadded in small portions and the reaction mixture was stirred at roomtemperature for 1 hour. The solvent was removed under reduced pressureand the product was without any further purification used in the nextstep.

LCMS method 2: MH⁺=287, RT=1.375 min

Preparation of Intermediate 47

A mixture of intermediate 46 (23.4 mmol), tert-butoxycarbonyl anhydride(5.62 g, 25.74 mmol) and triethylamine (3.892 ml, 28.08 mmol) intetrahydrofurane (70 ml) was stirred at 50° C. for 2 hours. The solventwas removed under reduced pressure. The residue was purified by flashcolumn chromatography over silica gel using dichloromethane and methanolas eluents. The product fractions were collected and the solvent wasevaporated.

Yield: 2.810 g of intermediate 47 (31%)

LCMS method 1: MH⁺=387, RT=1.063 min

Preparation of Intermediate 48

Intermediate 47 (2.810 g, 7.27 mmol) in a mixture of aceticacid/tetrahydrofuran/water (3:1:1, 22 ml) was stirred at 60° C.overnight. The solvent was removed under reduced pressure and theproduct was without any further purification used in the next step.

LCMS method 2: MH⁺=273, RT=1.274 min

Preparation of Intermediate 49

Sodium hydride (60% in mineral oil, 318 mg, 7.95 mg) was dissolved indry tetrahydrofuran under nitrogen atmosphere. Intermediate 48 (0.96 g,3.50 mmol) was added and the mixture was stirred at room temperature for15 minutes. 3-Bromo-5-chloro-pyrazolo[1,5-a]pyrimidine (0.74 g, 3.18mmol) was added and the mixture was stirred at room temperature for 30minutes. The solvent was removed under reduced pressure. The residue waspurified by flash column chromatography over silica gel usingdichloromethane and methanol as eluents. The product fractions werecollected and the solvent was evaporated.

Yield: 0.860 g of intermediate 49 (58%)

LCMS method 1: MH⁺=468, RT=0.834 min

Preparation of Intermediate 50

Intermediate 49 (0.86 g, 1.84 mmol) was dissolved in 4N hydrochloricacid solution in methanol (5.5 ml). The mixture was stirred at roomtemperature overnight. The solvent was removed under reduced pressureand the product was without any further purification used in the nextstep.

LCMS method 1: MH⁺=370, RT=0.178 min

Preparation of Intermediate 51

Intermediate 50 (1.84 mmol), triethylamine (0.559 ml, 5.52 mmol) and2-(tert-butyl(dimethyl)silyl)oxyacetaldehyde (0.38 ml, 2.02 mmol) weredissolved in dichloromethane (5.5 ml). Sodium triacetoxyborohydride(0.780 g, 3.68 mmol) was added in small portions and the mixture wasstirred at room temperature for 1 hour. The solvent was removed underreduced pressure. The residue was purified by flash columnchromatography over silica gel using dichloromethane and methanol aseluents. The product fractions were collected and the solvent wasevaporated.

LCMS method 1: MH⁺=526, RT=0.693 min

Preparation of Intermediate 52

A mixture of 1,4-dioxane and water (3:1, 8.5 ml) was degassed bybubbling nitrogen gas through the mixture. Intermediate 51 (0.449 g,0.85 mmol), (3-hydroxyphenyl)boronic acid (0.15 g, 1.11 mmol),tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (14 mg,0.03 mmol) and potassium phosphate tribasic (0.9 g, 5 eq.) were addedand the mixture was stirred under nitrogen gas at 80° C. for 2 hours.The reaction mixture was cooled, diluted with ethyl acetate and theorganic layer was washed with water and brine. The organic layer wasdried, filtered and the solvent was removed under reduced pressure. Theresidue was purified by flash column chromatography over silica gelusing heptane and ethyl acetate as eluents. The product fractions werecollected and the solvent was evaporated.

Yield: 0.23 g of intermediate 52 (50%)

LCMS method 2: MH⁺=540, RT=1.897 min

Preparation of Intermediate 53

Intermediate 52 (0.23 g, 0.43 mmol) in a mixture of aceticacid/tetrahydrofuran/water (3:1:1, 1.3 ml) was stirred at roomtemperature for 1 hour. Toluene was added and the solvent was removedunder reduced pressure and the product was without any furtherpurification used in the next step.

Yield: 0.14 g of intermediate 53 (77%)

LCMS method 2: MH⁺=426, RT=1.136 min

Preparation of Intermediate 54

Thionyl chloride (0.07 ml, 0.99 mmol) was added to a solution ofintermediate 53 (0.14 g, 0.33 mmol) and pyridine (80 μl, 0.99 mmol) indichloromethane (1 ml). The mixture was refluxed for 2 hours. Thesolvent was removed under reduced pressure and the product was withoutany further purification used in the next step.

LCMS method 1: MH⁺=444, RT=0.500 min

Preparation of Example 13

A solution of intermediate 53 (0.33 mmol) in 4N HCl in 1,4-dioxane (0.33mmol) was added drop wise to a solution of cesium carbonate (0.54 g,1.65 mmol) in N,N-dimethylformamide (1 ml) at 90° C. The mixture wasstirred at 90° C. for 2 hours. The solvent was removed under reducedpressure. The residue was purified by flash column chromatography oversilica gel using heptane and ethyl acetate as eluents. The productfractions were collected and the solvent was evaporated.

Yield: 51 g of example 13 (35%)

LCMS method 2: MH⁺=408, RT=1.926 min

Example 14

Example 13 is prepared following general scheme 1.

Preparation of Intermediate 55

2-(tert-Butyl(dimethyl)silyl)oxyacetaldehyde (1.527 ml, 8.24 mmol) wasadded to a solution of tert-butylN-[2-(2-aminoethyl(tert-butoxycarbonyl)amino)ethyl]carbamate (2.50 g,8.24 mmol) in methanol (25 ml). The mixture was stirred at roomtemperature for 30 minutes and sodium borohydride (0.312 g, 8.24 mmol)was added in small portions. The mixture was stirred at room temperaturefor 1 hour. 0.2 Equivalents of2-(tert-Butyl(dimethyl)silyl)oxyacetaldehyde was added and the mixturewas stirred at room temperature for 30 minutes. 0.22 Equivalents ofsodium borohydride and the mixture was stirred at room temperature for30 more minutes. A few drops of water were added and the solvent wasremoved under reduced pressure. The residue was purified by flashchromatography over silica gel using mixtures of dichloromethane andmethanol as eluents. The product fractions were collected and thesolvent was evaporated.

Yield: 3.06 mg of intermediate 55 (80%)

LCMS method 2: MH⁺=462, RT=1.899 min

Preparation of Intermediate 56

A mixture of 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine (1.5 g, 9.75mmol), intermediate 55 (3.0 g, 6.497 mmol) and N,N-diisopropylethylamine(2.263 ml, 12.99 mmol) in acetonitrile (19.5 ml) was stirred at 85° C.for 22 hours. 0.3 Equivalents of3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine was added and the mixture wasstirred at 90° C. for 22 hours. The reaction mixture was cooled and thesolvent was removed under reduced pressure. The residue was purified byflash column chromatography over silica gel using heptane and ethylacetate as eluents. The product fractions were collected and the solventwas evaporated.

Yield: 3.15 g of intermediate 56 (74%)

LCMS method 1: MH⁺=659, RT=2.398 min

Preparation of Intermediate 57

During the Suzuki coupling performed below, the compound was obtained inwhich the bromo was reduced. Subsequently a chlorogroup was introduced.

A mixture of N,N-dimethylformamide and water (3:1, 11.6 ml) was degassedby bubbling nitrogen gas through the mixture. Intermediate 56 (2.550 g,3.877 mmol), 3-boronobenzoic acid (0.966 g, 5.82 mmol),palladium(II)acetate (26 mg, 0.116 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (167 mg,0.35 mmol) and sodium carbonate (1.233 g, 3 eq.) were added and themixture was stirred under nitrogen gas at 80° C. overnight. The reactionmixture was cooled, water was added and the product was extracted withethyl acetate. The organic layer was dried, filtered and the solvent wasremoved under reduced pressure. The product obtained was the product inwhich the bromo of the starting material was reduced.

A solution of the product from the previous step (1.87 g, 3.231 mmol)was together with 1-chloropyrrolidine-2,5-dione (0.431 g, 3.23 mmol) inacetonitrile (10 ml) was stirred at room temperature for 4 hours. Thesolvent was removed under reduced pressure. The residue was purified byflash column chromatography over silica gel using heptane and ethylacetate as eluents. The product fractions were collected and the solventwas evaporated.

Yield: 0.45 g of intermediate 57 (23%)

LCMS method 1: MH⁺=613, RT=2.382 min

Preparation of Intermediate 58

A mixture of N,N-dimethylformamide and water (3:1, 3.5 ml) was degassedby bubbling nitrogen gas through the mixture. Intermediate 57 (0.350 g,0.571 mmol), 3-boronobenzoic acid (0.189 g, 1.14 mmol),palladium(II)acetate (7 mg, 0.029 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (38 mg,0.08 mmol) and sodium carbonate (3 eq.) were added and the mixture wasstirred under nitrogen gas at 80° C. overnight. 0.5 Equivalents of-boronobenzoic acid, palladium(II)acetate,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) were addedand the mixture was stirred at 80° C. for 6 hours. The reaction mixturewas cooled, water was added and the product was extracted with ethylacetate. The organic layer was dried, filtered and the solvent wasremoved under reduced pressure. The residue was purified by flash columnchromatography over silica gel using dichloromethane and methanol aseluents. The product fractions were collected and the solvent wasevaporated.

Yield: 0.112 g of intermediate 58 (30%)

LCMS method 1: MH⁺=699, RT=2.095 min

Preparation of Intermediate 59

Intermediate 58 (0.118 g, 0.169 mmol) was dissolved in 4N hydrochloricacid solution in 1,4-dioxane (0.5 ml). The mixture was stirred at roomtemperature for 2 hours. The solvent was removed under reduced pressureand the product was without any further purification used in the nextstep.

LCMS method 1: MH⁺=385, RT=0.288 min

Preparation of Example 14

A solution of intermediate 59 (97 mg, 0.23 mmol) inN,N-dimethylformamide (7 ml) was added dropwise to a solution ofN,N-diisopropylethylamine (0.40 ml, 2.30 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) (0.262 g, 0.69 mmol) in N,N-dimethylformamide (16 ml). Thereaction mixture was stirred at room temperature for 1 hour. The mixturewas quenched with an aqueous solution of ammonia (25%, 10 ml) and themixture was stirred at room temperature for 30 minutes. The solvent wasremoved under reduced pressure and the residue was purified by reversedphase column chromatography (HPLC method A). The product fractions werecollected and the solvent was evaporated.

Yield: 22 mg of example 14 (26%)

LCMS method 2: MH⁺=367, RT=1.201 min

Example 15

Example 15 is prepared following general scheme 1.

Preparation of Example 15

Molecular sieves were added to a solution of Example 14 (8 mg, 0.02mmol) in dry methanol (0.25 ml). Acetic acid (23 μl, 0.40 mmol),(1-ethoxycyclopropoxy)-trimethyl-silane (50 μl, 0.24 mmol) and sodiumcyanoborohydride (11 mg, 0.18 mmol) were added and the reaction mixturewas stirred at 70° C. for 18 hours. The solvent was removed underreduced pressure and the residue was purified by reversed phase columnchromatography (HPLC method A). The product fractions were collected andthe solvent was evaporated.

Yield: 2 mg of example 15 (8%)

LCMS method 2: MH⁺=407, RT=1.105 min

Example 16 Preparation of Example 16

Example 16 is prepared following general scheme 2.

Preparation of Intermediate 60

A mixture of 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine (10.2 g, 43.88mmol), N-(2-aminoethyl)-2-nitro-benzenesulfonamide hydrochloride (12.98g, 46.07 mmol) and N,N-diisopropylethylamine (22.387 ml, 131.64 mmol) inacetonitrile (131.64 ml) was refluxed for 10 hours. The reaction mixturewas cooled and concentrated under reduced pressure. The precipitate wasfiltered, washed with water, acetonitrile and diethyl ether. Thecompound was dried under reduced pressure and used in the next stepwithout further purification.

Yield: 16.8 g of intermediate 60 (87%)

LCMS method 1: MH⁺=442, RT=0.729 min

Preparation of Intermediate 61

A mixture of intermediate 60 (18.10 g, 41.02 mmol), tert-butoxycarbonylanhydride (8.95 g, 41.02 mmol) and 4-(dimethylamino)pyridine (250 mg,2.05 mmol) in tetrahydrofuran (123.06 ml) was stirred at 55° C. for 5hours. More tert-butoxycarbonyl anhydride (895 mg, 4.102 mmol) was addedand the reaction mixture was stirred at 55° C. for 5 hours. The reactionmixture was cooled and the solvent was removed under reduced pressure.The residue was purified by flash column chromatography over silica gelusing heptane and ethyl acetate as eluents (gradient elution from 10% to40% ethyl acetate). The product fractions were collected and the solventwas removed under reduced pressure.

Yield: 18.3 g of intermediate 61 (82%)

LCMS method 1: MH⁺=542, RT=1.028 min

Preparation of Intermediate 62

A mixture of intermediate 61 (12.70 g, 23.46 mmol), tert-butoxycarbonylanhydride (5.63 g, 25.81 mmol) and 4-(dimethylamino)pyridine (143 mg,1.17 mmol) in tetrahydrofuran (70.38 ml) was stirred at 55° C. for 5hours. The reaction mixture was cooled and the solvent was removed underreduced pressure. The residue was purified by flash columnchromatography over silica gel using heptane and ethyl acetate aseluents (gradient elution from 10% to 65% ethyl acetate). The productfractions were collected and the solvent was removed under reducedpressure. The residue was triturated with diethyl ether, filtered anddried under reduced pressure.

Yield: 14.7 g of intermediate 62 (98%)

LCMS method 2: MH⁺=642, RT=4.593 min

Preparation of Intermediate 63

A mixture of 1,4-dioxane and water (3:1, 9.36 ml) was degassed bybubbling nitrogen gas through the mixture. Intermediate 62 (2.00 g, 3.12mmol), [3-(tert-butoxycarbonylamino)phenyl]boronic acid (780 mg, 3.28mmol), tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (119 mg,0.25 mmol) and potassium phosphate tribasic (3.307 g, 5 eq.) were addedand the mixture was stirred under nitrogen gas at 80° C. for 18 hours.The reaction mixture was cooled and the solvent was removed underreduced pressure. Ethyl acetate was added and the organic layer waswashed with water. The organic layer was dried, filtered and the solventwas removed under reduced pressure. The product was used in the nextstep without further purification.

Preparation of Intermediate 64

Intermediate 63 (2.351 g, 3.12 mmol) was dissolved in 2N HCl in methanol(9.36 ml) and the mixture was stirred at room temperature for 2 hours.The solvent was removed under reduced pressure. The residue wastriturated with diethyl ether and the product was dried under reducedpressure. The residue was purified by flash column chromatography oversilica gel using dichloromethane and methanol as eluents (gradientelution from 0% to 50% methanol). The product fractions were collectedand the solvent was removed under reduced pressure.

Yield: 1.341 g of intermediate 63 (95%)

Preparation of Intermediate 65

A mixture of intermediate 64 (1.341 g, 2.96 mmol), methyl 2-bromoacetate(300 mg, 3.11 mmol) and cesium carbonate (1.157 g, 3.55 mmol) wasstirred overnight at 50° C. Water was added and the product wasextracted with ethyl acetate. The organic layer was washed with brine,dried, filtered and the solvent was removed under reduced pressure. Theresidue was purified by flash column chromatography over silica gelusing heptane and ethyl acetate as eluents (gradient elution from 0% to100% ethyl acetate). The product fractions were collected and thesolvent was removed under reduced pressure.

Yield: 1.321 g of intermediate 65 (85%)

LCMS method 1: MH⁺=526, RT=0.791 min

Preparation of Intermediate 66

Intermediate 65 (1.321 g, 2.51 mmol) and lithium hydroxide monohydrate(190 mg, 2.76 mmol) in a mixture tetrahydrofuran/methanol/water (2:2:1,7.53 ml) were stirred at room temperature for 2 hours. The solvent wasremoved under reduced pressure and the residue was used in the next stepwithout further purification.

LCMS method 2: MH⁺=512, RT=2.663 min

Preparation of Intermediate 67

A suspension of intermediate 66 (1.59 g, 3.08 mmol) inN,N-dimethylformamide (100 ml) was added drop wise to a solution ofO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) (3.50 g, 9.24 mmol) and N,N-diisopropylethylamine (3.143 ml,18.48 mmol) in N,N-dimethylformamide (200 ml). The mixture was stirredat room temperature for 1 hour. The reaction mixture was concentrated.Ethyl acetate was added and the organic layer was washed with asaturated aqueous sodium bicarbonate solution and brine. The organiclayer was dried, filtered and the solvent was removed under reducedpressure. The residue was purified by flash column chromatography oversilica gel using heptane and ethyl acetate as eluents (gradient elutionfrom 20% to 100% ethyl acetate). The product fractions were collectedand the solvent was removed under reduced pressure.

Yield: 290 mg of intermediate 67 (19%)

LCMS method 1: MH⁺=494

Preparation of Example 16

Cesium carbonate (384 mg, 1.18 mmol) and thiophenol (70 μl, 0.71 mmol)were suspended in N,N-dimethylformamide (1 ml) and the mixture wasstirred at room temperature for 15 minutes. A solution of intermediate66 (290 mg, 0.59 mmol) in N,N-dimethylformamide (1 ml) was added. Thereaction mixture was stirred at room temperature for 3 hours. Sodiumhydroxide (0.3 eq) was added and the solvent was removed under reducepressure. The residue was purified by reversed phase columnchromatography (HPLC method A). The product fractions were collected andthe solvent was removed under reduced pressure.

Yield: 40 mg of example 16 (22%)

LCMS method 2: MH⁺=309, RT=1.764 min

Example 17 Preparation of Example 17

Example 17 is prepared following general scheme 1.

Preparation of Intermediate 68

A mixture of 1,4-dioxane and water (3:1, 7.32 ml) was degassed bybubbling nitrogen gas through the mixture. Intermediate 23 (1.50 g, 2.44mmol), (3-hydroxy-4-methoxy-phenyl)boronic acid (430 mg, 2.56 mmol),tris(dibenzylideneacetone)dipalladium(0) (58 mg, 0.05 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (95 mg,0.20 mmol) and potassium phosphate tribasic (2.826 g, 5 eq.) were addedand the mixture was stirred under nitrogen gas at 80° C. for 18 hours.The reaction mixture was cooled, diluted with ethyl acetate and theorganic layer was washed with water and brine. The organic layer wasdried, filtered and the solvent was removed under reduced pressure. Theproduct was used in the next step without further purification.

Yield: 1.124 g of intermediate 68 (70%)

LCMS method 1: MH⁺=558 (MW-Boc), RT=1.517 min

Preparation of Intermediate 69

Tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 2.05 ml,2.05 mmol) was added to a solution of intermediate 68 (1.124 g, 1.71mmol) in tetrahydrofuran (5.13 ml) and the mixture was stirred at roomtemperature for 3 hours. The solvent was removed under reduced pressure.Ethyl acetate was added and the organic layer was washed with water andbrine. The organic layer was dried, filtered and the solvent was removedunder reduced pressure. The residue was purified by flash columnchromatography over silica gel using heptane and ethyl acetate aseluents. The product fractions were collected and the solvent wasevaporated.

Yield: 749 mg of intermediate 69 (81%)

LCMS method 1: MH⁺=444 (MW-Boc), RT=0.995 min

Preparation of Intermediate 70

A solution of intermediate 69 (749 mg, 1.38 mmol) in2-methyltetrahydrofuran (20 ml/mmol) and a solution of diisopropylazodicarboxylate (820 μl, 4.14 mmol) in toluene (20 ml/mmol) were addedsimultaneously to a solution of triphenylphosphine (1.086 g, 4.14 mmol)in toluene (75 ml/mmol of intermediate 68). The mixture was stirred at90° C. for 3 hours. The reaction mixture was cooled and the solvent wasremoved under reduced pressure. The residue was purified by flash columnchromatography over silica gel using heptane and ethyl acetate aseluents (gradient elution from 0% to 80% ethyl acetate). The productfractions were collected and the solvent was evaporated.

Yield: 441 g of intermediate 70 (61%)

Preparation of Example 17

Intermediate 70 (441 mg, 0.84 mmol) was dissolved in 4N hydrochloricacid in methanol (2.52 ml). The mixture was stirred at room temperaturefor 2 hours. The solvent was removed under reduced pressure. Theresulting solid was triturated in diethyl ether, filtered and driedunder reduced pressure.

Yield: 125 mg of example 17 (46%)

LCMS method 2: MH⁺=326, RT=1.636 min

Example 18 Preparation of Example 18

Example 18 is prepared following general scheme 1.

Preparation of Intermediate 71

Intermediate 70 was prepared according to the experimental proceduresfollowed to obtain intermediate 69, except that tert-butylN-(3-aminopropyl)-N-[2-(tert-butyl(dimethyl)silyl)oxyethyl]carbamate(prepared in the same way as intermediate 21) is being used for thecoupling to the scaffold and (3-hydroxyphenyl)boronic acid for theSuzuki coupling. The ring closure was performed following the methoddescribed to obtain intermediate 69.

Yield: 700 mg of intermediate 71 (92%)

LCMS method 1: MH⁺=510, RT=1.695 min

Preparation of Example 18

Intermediate 70 (700 mg, 1.37 mmol) was dissolved in 4N hydrochloricacid in methanol (4.11 ml). The mixture was stirred at room temperaturefor 2 hours. The solvent was removed under reduced pressure. Theresulting solid was triturated in diethyl ether, filtered and driedunder reduced pressure.

Yield: 387 mg of example 18 (82%)

LCMS method 2: MH⁺=310, RT=1.753 min

Example 19 Preparation of Example 19

Example 19 is prepared following general scheme 2.

Preparation of Intermediate 72

A mixture of 1,4-dioxane and water (3:1, 9.36 ml) was degassed bybubbling nitrogen gas through the mixture. Intermediate 62 (2.00 g, 3.12mmol), [3-[(tert-butoxycarbonylamino)methyl]phenyl]boronic acid (820 mg,3.28 mmol), tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (119 mg,0.25 mmol) and potassium phosphate tribasic (3.307 g, 5 eq.) were addedand the mixture was stirred under nitrogen gas at 80° C. for 18 hours.The reaction mixture was cooled and the solvent was removed underreduced pressure. Ethyl acetate was added and the organic layer waswashed with water. The organic layer was dried, filtered and the solventwas removed under reduced pressure. The residue was purified by flashcolumn chromatography over silica gel using heptane and ethyl acetate aseluents (gradient elution from 0% to 50% ethyl acetate). The productfractions were collected and the solvent was removed under reducedpressure.

Yield: 1.70 g of intermediate 72 (71%)

Preparation of Intermediate 73

Intermediate 72 (2.396 g, 3.12 mmol) was dissolved in 2N HCl in methanol(9.36 ml) and the mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure. The residue was trituratedwith diethyl ether and the product was dried under reduced pressure.

Yield: 1.174 g of intermediate 73 (80%)

Preparation of Intermediate 74

Tert-butoxycarbonyl anhydride (520 mg, 2.36 mmol) was added to asuspension of intermediate 73 (1.053 g, 2.25 mmol) in tetrahydrofuran(6.75 ml) and the mixture was stirred at room temperature for 4 hours.N,N-Diisopropylethylamine (383 μl, 2.25 mmol) was added and the reactionmixture was stirred at room temperature for 4 hours. Moretert-butoxycarbonyl anhydride (245 mg, 1.125 mmol) was added and thereaction mixture was stirred at room temperature for 4 hours. Thesolvent was removed under reduced pressure. Ethyl acetate was added andthe organic layer was washed with water and brine. The organic layer wasdried, filtered and the solvent was removed under reduced pressure. Theresidue was purified by flash column chromatography over silica gelusing heptane and ethyl acetate as eluents (gradient elution from 20% to80% ethyl acetate). The product fractions were collected and the solventwas removed under reduced pressure.

Yield: 450 mg of intermediate 74 (35%)

Preparation of Intermediate 75

Diisopropyl azodicarboxylate (184 μl, 0.93 mmol) was dissolved intetrahydrofuran (1.86 ml). Intermediate 74 (350 mg, 0.62 mmol) and ethyl2-hydroxyacetate (90 μl, 0.93 mmol) were added and the mixture wasstirred at room temperature for 15 minutes. Triphenylphosphine (244 mg,0.93 mmol) was added and the mixture was stirred at room temperatureovernight. Ethyl acetate was added and the organic layer was washed withwater and brine. The organic layer was dried, filtered and the solventwas removed under reduced pressure. The residue was purified by flashcolumn chromatography over silica gel using heptane and ethyl acetate aseluents (gradient elution from 0% to 100% ethyl acetate). The productfractions were collected and the solvent was removed under reducedpressure.

LCMS method 1: MH⁺=654, RT=1.063 min

Preparation of Intermediate 76

Intermediate 75 (558 mg, 0.85 mmol) was dissolved in a 4N HCl solutionin 1,4-dioxane (15 ml). The suspension was stirred at room temperatureovernight. The solvent was removed under reduced pressure and theresidue was used in the next step without further purification.

Preparation of Intermediate 77

Intermediate 76 (756 mg, 1.37 mmol) and lithium hydroxide monohydrate(60 mg, 1.51 mmol) in a mixture tetrahydrofuran/methanol/water (2:2:1,4.11 ml) were stirred at room temperature overnight. The solvent wasremoved under reduced pressure. The residue was purified by reversedphase HPLC (HPLC method A). The product fractions were collected and thesolvent was removed under reduced pressure.

Yield: 85 mg of intermediate 77 (12%)

Preparation of Intermediate 78

A suspension of intermediate 77 (85 mg, 0.16 mmol) inN,N-dimethylformamide (100 ml) was added drop wise to a solution ofO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) (180 mg, 0.48 mmol) and N,N-diisopropylethylamine (163 μl, 0.96mmol) in N,N-dimethylformamide (200 ml). The mixture was stirred at roomtemperature for 1 hour. Ethyl acetate was added and the organic layerwas washed with a saturated aqueous sodium bicarbonate solution andbrine. The organic layer was dried, filtered and the solvent was removedunder reduced pressure. The residue was purified by flash columnchromatography over silica gel using dichloromethane and a mixture ofdichlomethane/methanol (9:1) as eluents (gradient elution from 20% to100% dichlomethane/methanol (9:1)). The product fractions were collectedand the solvent was removed under reduced pressure.

Yield: 20 mg of intermediate 78 (25%)

LCMS method 1: MH⁺=508, RT=0.766 min

Preparation of Example 19

Cesium carbonate (26 mg, 0.08 mmol) and thiophenol (10 μl, 0.05 mmol)were suspended in N,N-dimethylformamide (60 μl) and the mixture wasstirred at room temperature for 15 minutes. A solution of intermediate81 (20 mg, 0.04 mmol) in N,N-dimethylformamide (60 μl) was added. Thereaction mixture was stirred at room temperature for 3 hours. Ethylacetate was added and the organic layer was washed with a 1N aqueoussodium hydroxide solution. The organic layer was dried, filtered and thesolvent was removed under reduce pressure. The residue was trituratedwith diethyl ether, filtered and the product was dried under reducedpressure.

Yield: 5 mg of example 19 (39%)

LCMS method 2: MH⁺=323, RT=1.515 min

Preparation of Example 20

Example 20 is prepared following general scheme 1.

O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) (656 mg, 1.73 mmol) was added to a suspension of example 1 (600mg, 1.73 mmol), 2-fluoroethanamine hydrochloride (170 mg, 1.73 mmol) andN,N-diisopropylethylamine (754 μl, 4.33 mmol) in N,N-dimethylformamide(10 ml). The mixture was stirred at room temperature for 5 hours. Thereaction mixture was concentrated under reduced pressure and ethylacetate was added. The organic layer was washed with water and the waterlayer was extracted with dichloromethane. The combined organic layerswere dried, filtered and the solvent was removed under reduced pressure.The residue was purified by reversed phase HPLC (HPLC method A). Theproduct fractions were collected and neutralized by addition of solidsodium carbonate. The product was extracted with dichloromethane. Thecombined organic layers were dried, filtered and the solvent was removedunder reduced pressure.

Yield: 28 mg of example 20 (4%)

LCMS method 2: MH⁺=386, RT=2.527 min

Preparation of Example 21

Example 21 is prepared following general scheme 1.

Preparation of Intermediate 79

Intermediate 79 was prepared according to the experimental proceduresfollowed to obtain intermediate 9, except that3-(2-aminoethoxyl)propan-1-ol is being used for the coupling to thescaffold and (3-fluoro-5-hydroxy-phenyl)boronic acid for the Suzukicoupling. The ring closure was performed following the method describedto obtain intermediate 9.

Yield: 430 mg of intermediate 79 (54%)

LCMS method 1: MH⁺=429, RT=1.291 min

Preparation of Example 21

Intermediate 79 (430 mg, 1.00 mmol) was dissolved in 4N hydrochloricacid in methanol (20 ml). The mixture was stirred at room temperaturefor 2 hours. The solvent was removed under reduced pressure. Theresulting solid was triturated in methanol, filtered and dried underreduced pressure.

Yield: 270 mg of example 21 (83%)

LCMS method 2: MH⁺=329, RT=3.347 min

The compounds in Table 1 were prepared by analogy to one of theprocedures described above.

TABLE 1

  Compound 1, Example 1

  Compound 2, Example 2

  Compound 3, Example 3

  Compound 4, Example 4

  Compound 5, Example 5

  Compound 6, Example 6

  Compound 7, Example 7

  Compound 8, Example 8

  Compound 9, Example 9

  Compound 10, Example 10

  Compound 11, Example 11

  Compound 12, Example 12

  Compound 13, Example 13

  Compound 14, Example 14

  Compound 15, Example 15

  Compound 16

  Compound 17

  Compound 18

  Compound 19

  Compound 20, Example 20

  Compound 21

  Compound 22

  Compound 23

  Compound 24

  Compound 25

  Compound 26

  Compound 27

  Compound 28

  Compound 29

  Compound 30

  Compound 31, Example 16

  Compound 32, Example 17

  Compound 33, Example 18

  Compound 34, Example 19

  Compound 35, Example 21Compound Identification

Melting Points

For the melting point determination of the compounds of the presentinvention, the following method was used.

Melting Point Method

For a number of compounds, melting points (m.p.) were determined in opencapillary tubes on a Mettler FP62 apparatus. Melting points weremeasured with a temperature ranging from 50° C. to 300° C., using agradient of 10° C./minute. The melting point value was read from adigital display and was not corrected.

TABLE 2 Melting points COMPOUND MELTING NUMBER POINT (° C.) 1 >3002 >300 3 >300 4 >300 5 >300 6 >300 7 271.6 8 283.9 9 287.6 10 >30011 >300 12 >300 13 >300 14 ND* 15 ND* 20 >300 31 ND* 32 ND* 33 ND* 34ND* 35 234.9 *Not determinedLCMS

For LCMS-characterization of the compounds of the present invention, thefollowing method was used.

General Procedure LCMS

All analyses were performed using an Agilent 6110 series LC/MSDquadrupole coupled to an Agilent 1290 series liquid chromatography (LC)system consisting of a binary pump with degasser, autosampler,thermostated column compartment and diode array detector. The massspectrometer (MS) was operated with an atmospheric pressureelectro-spray ionisation (API-ES) source in positive ion mode. Thecapillary voltage was set to 3000 V, the fragmentor voltage to 70 V andthe quadrupole temperature was maintained at 100° C. The drying gas flowand temperature values were 12.0 L/min and 350° C. respectively.Nitrogen was used as the nebulizer gas, at a pressure of 35 psig. Dataacquisition was performed with Agilent Chemstation software.

LCMS Method 1

In addition to the general procedure LCMS1: Analyses were carried out ona Phenomenex Kinetex C18 column (50 mm long×2.1 mm i.d.; 1.7 μmparticles) at 60° C., with a flow rate of 1.5 mL/min. A gradient elutionwas performed from 90% (water+0.1% formic acid)/10% Acetonitrile to 10%(water+0.1% formic acid)/90% acetonitrile in 1.50 minutes, then thefinal mobile phase composition was held for an additional 0.40 min. Thestandard injection volume was 2 μL. Acquisition ranges were set to 254nm for the UV-PDA detector and 80-800 m/z for the MS detector.

LCMS method 2

In addition to the general procedure LCMS1: Analyses were carried out ona YMC pack ODS-AQ C18 column (50 mm long×4.6 mm i.d.; 3 μm particles) at35° C., with a flow rate of 2.6 mL/min. A gradient elution was performedfrom 95% (water+0.1% formic acid)/5% Acetonitrile to 5% (water+0.1%formic acid)/95% Acetonitrile in 4.80 minutes, then the final mobilephase composition was held for an additional 1.00 min. The standardinjection volume was 2 μL. Acquisition ranges were set to 190-400 nm forthe UV-PDA detector and 100-1400 m/z for the MS detector.

TABLE 3 LCMS data COMPOUND MASS (MH)⁺ RETENTION LCMS NUMBER PEAK TIME(min) METHOD 1 341 2,252 2 2 421 1,650 2 3 309 2,181 2 4 339 1,245 2 5409 1,834 2 6 338 1,751 2 7 367 1,240 2 8 367 1,263 2 9 337 1,288 2 10451 1,180 2 11 410 1,131 2 12 327 2,223 2 13 408 1,926 2 14 367 1,201 215 407 1,105 2 20 386 2,527 2 31 309 1,764 2 32 326 1,636 2 33 310 1,7532 34 323 1,515 2 35 329 3,347 2B. Kinase Activity Assay

The inhibition of FLT3 kinase was assessed using FLT3 recombinantprotein in an in vitro peptide-based kinase assay.

Protocol 1

In a final reaction volume of 25 μL, Flt3 (h) (5-10 mU) is incubatedwith 8 mM MOPS pH 7.0, 0.2 mM EDTA, 50 μM EAIYAAPFAKKK, 10 mM MgAcetateand [g-33P-ATP] (specific activity approx. 500 cpm/pmol, concentrationas required). The reaction is initiated by the addition of the MgATPmix. After incubation for 40 minutes at room temperature, the reactionis stopped by the addition of 5 μL of a 3% phosphoric acid solution. 10μL of the reaction is then spotted onto a P30 filtermat and washed threetimes for 5 minutes in 75 mM phosphoric acid and once in methanol priorto drying and scintillation counting.

The inhibition of FLT3 D835Y mutant kinase was assessed using FLT3 D835Ymutant recombinant protein in an in vitro peptide-based kinase assay.

In a final reaction volume of 25 μL, Flt3 (D835Y) (h) (5-10 mU) isincubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 50 μM EAIYAAPFAKKK, 10 mMMgAcetate and [g-33P-ATP] (specific activity approx. 500 cpm/pmol,concentration as required). The reaction is initiated by the addition ofthe MgATP mix. After incubation for 40 minutes at room temperature, thereaction is stopped by the addition of 5 μL of a 3% phosphoric acidsolution. 10 μL of the reaction is then spotted onto a P30 filtermat andwashed three times for 5 minutes in 75 mM phosphoric acid and once inmethanol prior to drying and scintillation counting.

Protocol 2

A radiometric protein kinase assay (33PanQinase® Activity Assay) wasused for measuring the kinase activity. All kinase assays were performedin 96-well FlashPlates™ from PerkinElmer (Boston, Mass., USA) in a 50 μlreaction volume. The reaction cocktail was pipetted in four steps in thefollowing order:

-   -   20 μl of assay buffer (standard buffer)    -   5 μl of ATP solution (in H2O)    -   5 μl of test compound (in 10% DMSO)    -   10 μl of substrate/10 μl of enzyme solution (premixed)

The assay for FLT3 wt contains 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl2, 3 mMMnCl2, 3 μM Na-orthovanadate, 1.2 mM DTT, ATP (3 μM), [γ-33P]-ATP(approx. 5×1005 cpm per well), protein kinase FLT3 wt (6.1 nM) andsubstrate (poly(Ala,Glu,Lys,Tyr)6:2:5:1), 0.125 μg/50 μl).

The assay for FLT3 D835Y contains 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl2, 3mM MnCl2, 3 μM Na-orthovanadate, 1.2 mM DTT, ATP (0.3 μM), [γ-33P]-ATP(approx. 5×1005 cpm per well), protein kinase FLT3 D835Y (4.1 nM) andsubstrate (poly(Ala,Glu,Lys,Tyr)6:2:5:1), 0.5 μg/50 μl).

The kinases are obtained from Invitrogen Corporation.

The reaction cocktails were incubated at 30° C. for 60 minutes. Thereaction was stopped with 50 μl of 2% (v/v) H3PO4, plates were aspiratedand washed two times with 200 μl 0.9% (w/v) NaCl. Incorporation of 33Piwas determined with a microplate scintillation counter.

Table 4 provides the IC50 values of the compounds according to theinvention, obtained using the above mentioned kinase assay. COMPOUNDIC₅₀ for FLT3 IC₅₀ for FLT3 Protocol 1 +++ +++ 1 2 + + 1 3 +++ +++ 1 4+++ +++ 1 5 +++ +++ 1 6 +++ +++ 1 7 ++ ++ 1 8 +++ +++ 1 9 ++ +++ 1 10+++ +++ 1 11 ++ +++ 1 12 +++ +++ 1 13 + +++ 1 14 + ++ 1 15 ++ +++ 1 20ND* ND* 31 + + 2 32 ++ +++ 2 33 ++ +++ 2 34 + ++ 2 35 ND* ND* +indicates an IC50 > 1□M, ++ indicates an IC50 of between 100 nM and 1□M,and +++ indicates an IC50 < 100 nM *Not determined

The invention claimed is:
 1. A method for the treatment of acute myeloidleukemia (AML) or acute lymphocytic leukemia (ALL), said methodcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of Formula I or a stereoisomer, tautomer,racemic, pharmaceutically acceptable salt, or N-oxide form thereof; or apharmaceutical composition comprising the compound of Formula I,

wherein A₁ and A₂ are selected from C and N; wherein when A₁ is C, thenA₂ is N; and wherein when A₂ is C, then A₁ is N; R₁ and R₇ are eachindependently selected from —H, -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₉R₁₀, —(C═O)—R₄, —SO₂—R₄, —CN, —NR₉—SO₂—R₄,—C₃₋₆cycloalkyl, and -Het₆; wherein each of said C₁₋₆alkyl is optionallyand independently substituted with from 1 to 3 substituents selectedfrom -halo, —OH, —NR₁₁R₁₂, —O—C₁₋₆alkyl, and —S—C₁₋₆alkyl; R₂ isselected from —H, -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,—(C═O)—C₁₋₆alkyl, —(C═O)—O—C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈, -Het₃,—(C═O)-Het₃, —SO₂—C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,-Het₃, —Ar₂, and —NR₁₃R₁₄; R₃ is selected from —H, -halo, —OH,—C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl,—(C═O)—O—C₁₋₆alkyl, -Het₂, —C₃₋₆cycloalkyl, —(C═O)-Het₂, —(C═O)—NR₂₉R₃₀,and —SO₂—C₁₋₆alkyl; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from-halo, —OH, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —NR₁₅R₁₆, -Het₂, and —Ar₃; R₄ isindependently selected from -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —NR₁₇R₁₈, and -Het₄; R₅ is selected from —H —C₁₋₆alkyl,and —C₃₋₆cycloalkyl; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from-halo, —OH, —OC₁₋₆alkyl, —SC₁₋₆alkyl, -Het₅, and —NR₃₁R₃₂; R₆ isselected from —H, —OH, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,—NR₃₃R₃₄, and -Het₈; R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂,R₃₃, and R₃₄ are each independently selected from —H, —O, —C₁₋₆alkyl,and Het₁; wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH,—O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —NR₃₅R₃₆, -Het₇, and —Ar₄; R₃₅ and R₃₆ areeach independently selected from —H, —O, and C₁₋₆alkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —O—C₁₋₆alkyl, and—S—C₁₋₆alkyl; X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-,—S—C₁₋₆alkyl-, —(C═O)—, —NR₃—(C═O)—, —C₁₋₆alkyl-NR₃—(C═O)—,—NR₃—(C═O)—NR₃₅—, —NR₃—C₁₋₆alkyl-, —NR₃—, and —NR₃—SO₂—; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, and —NR₂₃R₂₄; X₂ is selected from —C₁₋₆alkyl-,—O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-, —(C═O)—, —NR₂—(C═O)—, —NR₂—C₁₋₆alkyl-,—NR₂—, and —SO₂—NR₂—; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from-halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, and —NR₂₅R₂₆; Y isselected from a direct bond, —CHR₆—, —O—, —S—, and —NR₅—; Ar₂, Ar₃, andAr₄ are each independently a 5- or 6-membered aryl optionally comprising1 or 2 heteroatoms selected from O, N and S; wherein each of said Ar₂,Ar₃, and Ar₄ is optionally and independently substituted with from 1 to3 substituents selected from —NR₁₉R₂₀, —C₁₋₆alkyl, —O—C₁₋₆alkyl, and—S—C₁₋₆alkyl; Het₁, Het₂, Het₃, Het₄, Het₅, Het₆, Het₇ and Het₈ are eachindependently a 5- or 6-membered monocyclic heterocycle having from 1 to3 heteroatoms selected from O, N and S, wherein each heterocycle isoptionally substituted with from 1 to 3 substituents selected from—C₁₋₆alkyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, and —NR₂₁R₂₂; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3-halo; Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C andN; and m and n are each independently 1, 2, 3, or
 4. 2. The methodaccording to claim 1, wherein: A₁ and A₂ are selected from C and N;wherein when A₁ is C, then A₂ is N; and wherein when A₂ is C, then A₁ isN; R₁ is selected from —H, -halo, —OH, —C₁₋₆alkyl, —O—C₁₋₆alkyl,—NR₉R₁₀, —(C═O)—R₄, —CN, —NR₉—SO₂—R₄, and -Het₆; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, and —NR₁₁R₁₂; R₇ is selected from—H, and -halo; R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈,—(C═O)-Het₃, and —SO₂—C₁₋₆alkyl; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, —OH, —O—C₁₋₆alkyl, -Het₃, and —NR₁₃R₁₄; R₃ isselected from —H, —C₁₋₆alkyl, —(C═O)—C₁₋₆alkyl, —(C═O)-Het₂,—(C═O)—NR₂₉R₃₀, and —SO₂—C₁₋₆alkyl; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, —OH, and —O—C₁₋₆alkyl; R₄ is independently selectedfrom —OH, —O—C₁₋₆alkyl, —NR₁₇R₁₈, and -Het₄; R₅ is selected from —H,—C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, —OH, —OC₁₋₆alkyl, -Het₅, and —NR₃₁R₃₂; R₆ isselected from —OH, and —NR₃₃R₃₄; R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₇, R₁₈,R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, and R₃₄ are each independentlyselected from —H, —C₁₋₆alkyl, —NR₃₅R₃₆ or Het₁; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, and -Het₇; R₃₅ and R₃₆ are eachindependently selected from —H, —O, and C₁₋₆alkyl; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —O—C₁₋₆alkyl, and —S—C₁₋₆alkyl;X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-, —(C═O)—,—NR₃—(C═O)—, —C₁₋₆alkyl-NR₃—(C═O)—, —NR₃—(C═O)—NR₃₅—, —NR₃—C₁₋₆alkyl-,and —NR₃—SO₂—; X₂ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-,—(C═O)—NR₂—, and —NR₂—C₁₋₆alkyl-; Y is selected from a direct bond,—CHR₆—, —O—, —S—, and —NR₅—; Het₁, Het₂, Het₃, Het₄, Het₅, Het₆, andHet₇ are each independently a 5- or 6-membered monocyclic heterocyclehaving from 1 to 3 heteroatoms selected from O, N and S, wherein eachheterocycle is being optionally substituted with from 1 to 3 —C₁₋₆alkyl;each of said C₁₋₆alkyl being optionally and independently substitutedwith from 1 to 3 -halo Z₁, Z₂, Z₃, Z₄ and Z₅ are each independentlyselected from C and N; and m and n are each independently 1, 2, 3, or 4.3. The method according to claim 1, wherein: A₁ and A₂ are selected fromC and N; wherein when A₁ is C, then A₂ is N; and wherein when A₂ is C,then A₁ is N; R₁ is selected from —H, -halo, —OH, —C₁₋₂alkyl,—O—C₁₋₂alkyl, —NR₉R₁₀, —(C═O)—R₄, —CN, —NR₉—SO₂—R₄, and -Het₆; whereineach of said C₁₋₂alkyl is optionally and independently substituted withfrom 1 to 3 substituents selected from -halo, —OH, and —NR₁₁R₁₂; R₇ isselected from —H, and -halo; R₂ is selected from —H, —C₁₋₃alkyl,—(C═O)—NR₂₇R₂₈, —(C═O)-Het₃, and —SO₂—C₁₋₃alkyl; wherein each of saidC₁₋₃alkyl is optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —O—CH₃, -Het₃, and —NR₁₃R₁₄; R₃is selected from —H, —C₁₋₂alkyl, —(C═O)—C₁₋₂alkyl, —(C═O)-Het₂,—(C═O)—NR₂₉R₃₀, and —SO₂—C₁₋₂alkyl; wherein each of said C₁₋₂alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, —OH, and —O—CH₃; R₄ is selected from —OH, —O—CH₃,—NR₁₇R₁₈, and -Het₄; R₅ is selected from —H —C₁₋₃alkyl, and—C₃₋₆cycloalkyl; wherein each of said C₁₋₃alkyl is optionally andindependently substituted with from 1 to 3 substituents selected from-halo, —OH, —OCH₃, -Het₅, and —NR₃₁R₃₂; R₆ is selected from —OH, and—NR₃₃R₃₄; R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₃₁, R₃₂, R₃₃, and R₃₄ are eachindependently selected from —H and —CH₃; R₁₇, R₁₈, R₂₇, and R₂₈ are eachindependently selected from —H and —C₁₋₂alkyl, each of said —C₁₋₂alkylbeing optionally and independently substituted with from 1 to 3substituents selected from —OH, -halo —NR₃₅R₃₆ and -Het₇; R₂₉ and R₃₀,are each independently selected from —H, —OH and —OCH₃; R₃₅ and R₃₆ areeach independently selected from —H, —O, and C₁₋₆alkyl; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from -halo, —OH, —O—C₁₋₆alkyl, and—S—C₁₋₆alkyl; X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —(C═O)—,—S—C₁₋₆alkyl-, —NR₃—(C═O)—, —C₁₋₆alkyl-NR₃—(C═O)—, —NR₃—(C═O)—NR₃₅—,—NR₃—C₁₋₆alkyl-, and —NR₃—SO₂—C₁₋₆alkyl-; X₂ is selected from—C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₆alkyl-; Y isselected from a direct bond, —CHR₆—, —O—, —S—, and —NR₅—; Het₁ isselected from -piperidinyl and -piperazinyl; each of said Het₁ beingsubstituted with C₁₋₂alkyl; each of said C₁₋₂alkyl being optionally andindependently substituted with from 1 to 3 -halo; Het₂ is-piperidinyl-CH₃; Het₃ is selected from -piperazinyl, and -morpholinyl;Het₄, is selected from -piperazinyl, and -morpholinyl; each of said Het₄being optionally and independently substituted with C₁₋₂alkyl; each ofsaid C₁₋₂alkyl being optionally and independently substituted with from1 to 3 -halo; Het₅ is -morpholinyl; Het₆, is -piperazinyl; Het₇ is-pyrrolidinyl; Z₁, Z₂, Z₃, Z₄ and Z₅ are each independently selectedfrom C and N; and m and n are each independently 1, 2, 3, or
 4. 4. Themethod according to claim 1, wherein: A₁ and A₂ are selected from C andN; wherein when A₁ is C, then A₂ is N; and wherein when A₂ is C, then A₁is N; R₁ is selected from —H, -halo, —C₁₋₆alkyl, —OC₁₋₆alkyl, and—(C═O)—R₄; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 -halo; R₇ is —H; R₂ isselected from —H, —C₁₋₆alkyl, —(C═O)—O—C₁₋₆alkyl, and —(C═O)-Het₃;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from —OH,—OC₁₋₆alkyl, -Het₃, and —NR₁₃R₁₄; R₃ is selected from —H, —C₁₋₆alkyl,and —(C═O)-Het₂; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 substituents —OH; R₄ isselected from —OH, —O—C₁₋₆alkyl, —NR₁₇R₁₈, and -Het₄; R₅ is selectedfrom —H, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each of said C₁₋₆alkylis optionally and independently substituted with from 1 to 3substituents selected from —OH, and -Het₅; R₁₃, R₁₄, R₁₇, R₁₈, R₁₉ andR₂₀ are each independently selected from —H, —O, —C₁₋₆alkyl, and Het₁;X₁ is selected from —C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —NR₃—(C═O)—,—C₁₋₆alkyl-NR₃—(C═O)—, and —NR₃—C₁₋₆alkyl-; X₂ is selected from—O—C₁₋₆alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₆alkyl-; Y is selected from adirect bond, —O—, —S—, and —NR₅—; Het₁, Het₂, Het₃, Het₄ and Het₅ areeach independently a 5- or 6-membered monocyclic heterocycle having from1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle isbeing optionally substituted with from 1 to 3 —C₁₋₆alkyl; Z₁, Z₂, Z₃, Z₄and Z₅ are each independently selected from C and N; and m and n areeach independently 1, 2, 3, or
 4. 5. The method according to claim 1,wherein: A₁ and A₂ are selected from C and N; wherein when A₁ is C, thenA₂ is N; and wherein when A₂ is C, then A₁ is N R₁ is selected from —H,-halo, —CF₃, —OC₁₋₆alkyl, and —(C═O)—R₄; R₇ is —H; R₂ is selected from—H, —C₁₋₆alkyl, —(C═O)—O—C₁₋₆alkyl, and —(C═O)-Het₃; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 substituents selected from —OH, —OC₁₋₆alkyl, -Het₃, and —NR₁₃R₁₄;R₃ is selected from —H, —C₁₋₆alkyl, and —(C═O)-Het₂; wherein each ofsaid C₁₋₆alkyl is optionally and independently substituted with from 1to 3 —OH; R₄ is selected from —OH, —OC₁₋₆alkyl, —NR₁₇R₁₈, and -Het₄; R₅is selected from —H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from —OH, and -Het₅; R₁₃ and R₁₄ are eachindependently selected from —H, and —C₁₋₆alkyl; R₁₇ and R₁₈ are eachindependently selected from —H, —C₁₋₆alkyl, and -Het₁; R₁₉ and R₂₀ areeach independently selected from —O, and —C₁₋₆alkyl; X₁ is selected from—C₁₋₆alkyl-, —O—C₁₋₆alkyl-, —NR₃—(C═O)—, —C₁₋₆alkyl-NR₃—(C═O)—, and—NR₃—C₁₋₆alkyl-; X₂ is selected from —O—C₁₋₆alkyl-, —(C═O)—NR₂—, and—NR₂—C₁₋₆alkyl-; Y is selected from a direct bond, —O—, —S—, and —NR₅—;Het₁, Het₂, Het₃, Het₄ and Het₅ are each independently selected from-morpholinyl, -piperidinyl, -piperazinyl, and pyrrolidinyl, wherein eachheterocycle is optionally substituted with from 1 to 3 —C₁₋₆alkyl; Z₁,Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N; and mand n are each independently 1, 2, 3, or
 4. 6. The method according toclaim 1, wherein: A₁ and A₂ are selected from C and N; wherein when A₁is C, then A₂ is N; and wherein when A₂ is C, then A₁ is N R₁ isselected from —H, -halo, —CF₃, —OCH₃, and —(C═O)—R₄; R₇ is —H; R₂ isselected from —H, —C₂₋₄alkyl, —(C═O)—O—C₂₋₄alkyl, and —(C═O)-Het₃;wherein each of said C₂₋₄alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from —OH, —OCH₃,-Het₃, and —NR₁₃R₁₄; R₃ is selected from —H, —C₁₋₂alkyl, and—(C═O)-Het₂; wherein each of said C₁₋₂alkyl is optionally andindependently substituted with from 1 to 3 —OH; R₄ is selected from —OH,—OCH₃, —NR₁₇R₁₈, and -Het₄; R₅ is selected from —H, —C₁₋₃alkyl, and—C₃₋₆cycloalkyl; wherein each C₁₋₃alkyl is optionally substituted withfrom 1 to 3 substituents selected from —OH, and -Het₅; R₁₃ and R₁₄ are—CH₃; R₁₇ and R₁₈ are each independently selected from —H, —CH₃, and-Het₁; R₁₉ and R₂₀ are each —O; X₁ is selected from —C₁₋₆alkyl-,—O—C₂₋₆alkyl-, —NR₃—(C═O)—, —C₁₋₆alkyl-NR₃—(C═O)—, and —NR₃—C₂₋₃alkyl-;X₂ is selected from —O—C₂alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₃alkyl-; Y isselected from a direct bond, —O—, —S—, and —NR₅—; Het₁, Het₂, Het₃, Het₄and Het₅ are each independently selected from -morpholinyl,-piperidinyl, -piperazinyl, and pyrrolidinyl, wherein each heterocycleis optionally substituted with from 1 to 3 —CH₃; Z₁, Z₂, Z₃, Z₄ and Z₅are each independently selected from C and N; and m and n are eachindependently 1, 2, 3, or
 4. 7. The method according to claim 1,wherein: A₁ and A₂ are selected from C and N; wherein when A₁ is C, thenA₂ is N; and wherein when A₂ is C, then A₁ is N; R₁ is selected from —H,-halo, —CF₃, —OCH₃, —(C═O)—OH, —(C═O)—OCH₃, —(C═O)-Het₄, —(C═O)—NH-Het₄,—(C═O)—NH₂, and —(C═O)—NH—CH₃; R₇ is —H; R₂ is selected from —H,—C₂₋₄alkyl, —(C═O)—O—C₂alkyl, and —(C═O)-Het₃; wherein each C₂₋₄alkyl isoptionally and independently substituted with 1 substituent selectedfrom —OH, —OCH₃, -Het₃, and —NR₁₃R₁₄; R₃ is selected from —H,—C₁₋₂alkyl, and —(C═O)-Het₂; wherein said C₁₋₂alkyl is optionally andindependently substituted with 1 —OH; R₅ is selected from —H,—C₁₋₃alkyl, and —C₃₋₆cycloalkyl; wherein each C₁₋₃alkyl is optionallyand independently substituted with 1 to 3 substituents selected from—OH, and -Het₅; R₁₃ and R₁₄ are —CH₃; X₁ is selected from —C₁₋₆alkyl-,—O—C₂₋₆alkyl-, —NR₃—(C═O)—, —C₁₋₆alkyl-NR₃—(C═O)—, and —NR₃—C₂alkyl-; X₂is selected from —O—C₂alkyl-, —(C═O)—NR₂—, and —NR₂—C₁₋₃alkyl-; Y isselected from a direct bond, —O—, —S—, and —NR₅—; Ar₃ is phenylsubstituted with —NO₂; Het₂ is -piperidinyl substituted with —CH₃; Het₃is selected from -morpholinyl, and -piperazinyl; Het₄ is selected from-morpholinyl, -piperidinyl, and -piperazinyl; wherein said -piperidinyland -piperazinyl are substituted with —CH₃; Het₅ is selected from-morpholinyl, and -pyrrolidinyl; Z₁, Z₂, Z₃, Z₄ and Z₅ are eachindependently selected from C and N; and m and n are each independently1, 2, 3, or
 4. 8. The method according to claim 1, wherein: A₁ and A₂are selected from C and N; wherein when A₁ is C, then A₂ is N; andwherein when A₂ is C, then A₁ is N; R₁ and R₇ are each independentlyselected from —H, -halo, —C₁₋₆alkyl, —O—C₁₋₆alkyl, and —(C═O)—R₄;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, and —OH;R₂ is selected from —H, —C₁₋₆alkyl, —(C═O)—NR₂₇R₂₈, and —(C═O)-Het₃;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH, and—NR₁₃R₁₄; R₃ is selected from —H, —C₁₋₆alkyl, and —(C═O)-Het₂; whereineach of said C₁₋₆alkyl is optionally and independently substituted with—OH; R₄ is independently selected from —OH, and —NR₁₇R₁₈; R₅ is selectedfrom —H —C₁₋₆alkyl, and —C₃₋₆cycloalkyl; wherein each of said C₁₋₆alkylis optionally and independently substituted with from 1 to 3substituents selected from -halo, —OH, —OC₁₋₆alkyl, -Het₅, and —NR₃₁R₃₂;R₁₃, R₁₄, R₁₇, R₁₈, R₂₇, R₂₈, R₃₁, and R₃₂ are each independentlyselected from —H, and —C₁₋₆alkyl; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from -halo, —NR₃₅R₃₆, and -Het₇; R₃₅ and R₃₆ are each—C₁₋₆alkyl; X₁ is selected from —O—C₁₋₆alkyl-, —(C═O)—, —NR₃—(C═O)—,—C₁₋₆alkyl-NR₃—(C═O)—, and —NR₃—; X₂ is selected from —O—C₁₋₆alkyl-, and—NR₂—; Y is selected from a direct bond, —O—, and —NR₅—; Het₃ is-piperazinyl Het₂ is -piperidinyl substituted with —CH₃; Het₅ isselected from -morpholinyl and -pyrrolidinyl; Het₇ is -pyrrolidinyl; Z₁,Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N; and mand n are each independently 1, 2, 3, or
 4. 9. The method according toclaim 1, wherein: A₁ is N; and A₂ is C; R₁ and R₇ are each independentlyselected from —H, —C₁₋₆alkyl, —O—C₁₋₆alkyl, and —(C═O)—R₄; wherein eachof said C₁₋₆alkyl is optionally and independently substituted with from1 to 3 substituents selected from -halo, and —OH; R₂ is selected from—H, —C₁₋₆alkyl, and —(C═O)—NR₂₇R₂₈; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from —OH; R₃ is selected from —H, —C₁₋₆alkyl, and —(C═O)-Het₂;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with —OH; R₄ is independently selected from —OH, and—NR₁₇R₁₈; R₅ is selected from —H —C₁₋₆alkyl, and —C₃₋₆cycloalkyl;wherein each of said C₁₋₆alkyl is optionally and independentlysubstituted with from 1 to 3 substituents selected from -halo, —OH,—OC₁₋₆alkyl, and -Het₅; R₁₇, R₁₈, R₂₇, and R₂₈ are each independentlyselected from —H, and —C₁₋₆alkyl; wherein each of said C₁₋₆alkyl isoptionally and independently substituted with from 1 to 3 substituentsselected from —NR₃₅R₃₆, and -Het₇; R₃₅ and R₃₆ are each —C₁₋₆alkyl; X₁is selected from —O—C₁₋₆alkyl-, —NR₃—(C═O)—, and —NR₃—; X₂ is selectedfrom —O—C₁₋₆alkyl-, and —NR₂—; Y is selected from a direct bond, —O—,and —NR₅—; Het₂ is -piperidinyl substituted with —CH₃; Het₅ is selectedfrom -morpholinyl and -pyrrolidinyl; Het₇ is -pyrrolidinyl; Z₁, Z₂, Z₃,Z₄ and Z₅ are each C; and m and n are each independently 1, 2, 3, or 4.10. The method according to claim 1, wherein: A₁ is N; and A₂ is C; R₁and R₇ are each —H; R₂ is selected from —H, —(C═O)—NR₂₇R₂₈ and—C₁₋₆alkyl; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 —OH; R₅ is selected from —Hand —C₁₋₆alkyl; wherein each of said C₁₋₆alkyl is optionally andindependently substituted with from 1 to 3 -Het₅; R₂₇, and R₂₈ are eachindependently selected from —H, and —C₁₋₆alkyl; wherein each of saidC₁₋₆alkyl is optionally and independently substituted with from 1 to 3substituents selected from —NR₃₅R₃₆, and -Het₇; R₃₅ and R₃₆ are each—C₁₋₆alkyl; X₁ is —O—CH₂—; X₂ is selected from —O—CH₂—, and —NR₂—; Y is—NR₅—; Het₅ is selected from -morpholinyl and -pyrrolidinyl; Het₇ is-pyrrolidinyl; Z₁, Z₂, Z₃, Z₄ and Z₅ are each C; m is 1; and n isselected from 1, 2 and
 3. 11. The method according to claim 1, whereinsaid compound is selected from the group consisting of:


12. The method according to claim 1, wherein the bicyclic ringcontaining A₁ and A₂ is linked to the ring containing Z₁-Z₅ at positionZ₄ and wherein R₇ is linked to the ring containing Z₁-Z₅ at position Z₅in accordance with Formula I.